9.5.1: Cost and Prevention of Resistance - Biology

9.5.1: Cost and Prevention of Resistance - Biology

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Learning Objectives

  • Examine the causes and effects of multidrug-resistant organisms on healthcare

Prevention and control of microbial-resistant organisms is one of the most complex management issues that health care professionals face. The clinical and financial burden to patients and health care providers is staggering. Patients who are infected with bacterial strains resistant to more than one type or class of drugs (multidrug-resistant organisms, MDRO) often have an increased risk of prolonged illness, extended hospital stay, and mortality.

The cost of care for these patients can be more than double compared to those without an MDRO infection. The alternative medication they are prescribed to overcome the infection is often substantially more costly. Multidrug resistance forces healthcare providers to use antibiotics that are more expensive or more toxic to the patient.

When no antibiotic is effective, healthcare providers may be limited to providing supportive care rather than directly treating an infection. In a 2008 study of attributable medical costs for antibiotic resistant infections, it was estimated that infections in 188 patients from a single healthcare institution cost between $13.35 and $18.75 million dollars.

Research and development of new drugs effective against resistant bacterial strains also comes at a cost. To prevent antimicrobial resistance, the patient and the healthcare provider should discuss the appropriate medicine for the illness. Patients should follow prescription directions and should not share or take medicine that was prescribed for someone else; these virtues should be strictly practiced. Healthy lifestyle habits, including proper diet, exercise, and sleeping patterns, as well as good hygiene such as frequent hand washing, can help prevent illness. These practices, therefore, also help prevent the overuse or misuse of antibiotics and the emergence of problematic resistant strains.

There are also several actions that can be taken by the medical community to help prevent the development and spread of antibiotic resistance:

  • Prevent infections whenever possible through vaccination and other appropriate protective measures.
  • Prescribe narrow-spectrum as opposed to broad-spectrum antibiotics whenever possible. In this way, fewer groups of bacteria will be exposed to selective pressure that will result in resistance.
  • Keep certain drugs as "drugs of last resort" to be used in only the most desperate cases to reduce the exposure of microbes to these drugs.
  • Only prescribe antimicrobial drugs when they are truly necessary. Avoid prescribing antibiotics for viral infections or minor infections that can self-resolve and try other treatments in place of antimicrobial drugs if they are available.
  • Use drugs in combinations. Although a pathogen might develop resistance to one drug, the other drug(s) in the combination will still be able to control it. This is a common strategy for treatment of HIV and tuberculosis.
  • In cases where treatment compliance is an issue, directly observed therapy (DOT) is sometimes used. This involves health workers administering the prescribed drugs and confirming they are taken properly. DOT has been most widely applied for treatment of tuberculosis due to its long treatment period and generally lower compliance in treatment.
  • Select antibiotics that are less likely to lead to resistance, such as those shown to be difficult to develop resistance to and those which do not persist in the environment.

Other industries also contribute to and can play a role in preventing antibiotic resistance. Agriculture and aquaculture use large amounts of antibiotics which are released into the environment and can lead to development of antibiotic resistance. There is no barrier between human pathogens and environmental bacteria, making non-pathogenic environmental bacteria a potential reservoir of antibiotic resistance. For instance, it is thought that vancomycin resistant Enterococcus first appeared as a result of the use of vancomycin-like antibiotics used in cattle. Recent governmental regulations have attempted to reduce this risk by restricting antibiotics in agriculture to therapetuic use.

Key Points

  • Antimicrobial resistance to available drugs requires the development of new drugs to effectively treat resistant strains and reduce mortality from bacterial infections.
  • Antimicrobial resistance can be prevented by practicing good hygiene, and being responsible with antibiotic use.
  • Treating antibiotic-resistant bacterial strains is expensive for both the patient and the healthcare provider. The treatment requires extended hospital stay and costly medications.

Key Terms

  • multidrug resistance: A condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism.

Understanding and overcoming antibiotic resistance

Copyright: © 2017 Lauren A. Richardson. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing interests: LR is a current paid employee at Public Library of Science.

Provenance: Written by editorial staff not externally peer reviewed

Antibiotic drugs have revolutionized medicine and made our modern way of life possible. In addition to their essential role in the clinic, antibiotics are used in a huge array of non-medical applications, from promoting growth in livestock, to preserving building materials from contamination, to treating blight in orchards. However, overuse threatens their efficacy due to the promotion and spread of antibiotic resistant bacteria.

Antibiotics target and inhibit essential cellular processes, retarding growth and causing cell death. However, if bacteria are exposed to drugs below the dose required to kill all bacteria in a population (the minimum bactericidal concentration or MBC), they can mutate and resist antibiotic treatment via natural selection for resistance-conferring mutations. These genetic mutations can arise from the adoption of a plasmid encoding a resistance gene or by mutation to the bacterial chromosome itself.

The concern around the increasing prevalence of drug resistant bacteria is compounded by the fact that the discovery of new antibiotics is a fleeting rare event. Most classes of antibiotics on the market were discovered in the mid-to-late 20 th century. Thus, there is a limited arsenal of drugs to fight resistant bacteria, and bacteria can be resistant to multiple drugs at a time.

Given the importance of antibiotics to modern medicine, and the growing apprehension surrounding the threat of resistance, scientists are studying every aspect of antibiotic resistance. This Open Highlight features some of the cutting-edge research from the Open Access corpus on three major areas of focus: the cellular mechanisms of resistance, the evolution and spread of resistance, and techniques for combating resistance.

Antibiotic resistance is one of the world’s most urgent public health problems affecting people at any stage of life. According to data from the CDC (Center for Disease Control and Prevention), a major contributing factor to antibiotic resistance is the over-prescription of antibiotics - typically prescribed for misdiagnosed illnesses caused by viruses, which do not respond to antibiotics. Since medical costs and antibiotic resistance-related deaths are rising each year, the need for faster diagnoses and precise treatment options to combat antibiotic resistance is evident. Source

Billion Dollar-cost

In 2011, there were approximately 400,000 hospitalizations for UTIs with an estimated cost of $2.8 billion. Source

Million excess prescriptions

30% of antibiotics prescribed in the United State are unnecessary. This totals 47 million excess prescriptions. Source

Thousand deaths related to antibiotic-resistance

Each year in the United States, at least 2 million people are infected with antibiotic-resistant bacteria, and at least 23,000 people die as a result. Source


Despite the decline in the prevalence of dental caries in children in the western countries, caries in pre-school children remains a problem in both developed and developing countries. ECC has been considered to be at epidemic proportions in the developing countries.[4,17]

A comprehensive review of the occurrence of the caries on maxillary anterior teeth in children, including numerous studies from Europe, Africa, Asia, the Middle East, and North America, found the highest caries prevalence in Africa and South-East Asia.[18] The prevalence of ECC is estimated to range from 1 to 12% in infants from developed countries.[19]

Prevalence of ECC is a not a common finding relative to some European countries (England, Sweden, and Finland), with the available prevalence data ranging from below 1% to 32%.[20,21] However, this figure is rising by as much as 56% in some eastern European countries.[22] In US, pre-school children data from a more recent study indicate that the prevalence of dental caries of children 2𠄵 years of age had increased from 24% in 1988� to 28% in 1999�. Overall, considering all 2𠄵-year olds, the 1999-2004 survey indicates that 72% of decayed or filled tooth surfaces remain untreated.[14,23,24] The prevalence of ECC children in the general population of Canada is less than 5% but in high-risk population, 50�% are affected.[25,26,27] Studies reveal that the prevalence percentage of ECC in 25- to 36-month olds[28] is 46% and the reported prevalence in Native Canadian 3-year-olds[29] has been as high as 65%.

Published studies show higher prevalence figures for 3-year-olds, which ranges from 36 to 85%[30�] in Far East Asia region, whereas this figure is 44% for 8- to 48-month olds[33] reported in Indian studies. ECC has been considered at epidemic proportions in the developing countries.[34] Studies conducted in the Middle East have shown that the prevalence of dental caries in 3-year-olds is between 22% and 61%[35�] and in Africa it is between 38% and 45%.[38,39]

Postprandial hepatic metabolite fluxes

Fasting hyperglycaemia in T2D results from increased rates of hepatic gluconeogenesis and EGP and from hepatic insulin resistance, characterized by reduced ability of insulin to suppress this process 38,39,40,41 . This may be because of direct IR-mediated cell-autonomous or indirect effects (substrate availability, allosteric regulation or redox status) 42 (Fig. 1b). Recent studies showed that these indirect effects probably result from insulin action on WAT and mainly account for acute suppression of gluconeogenesis and EGP during postprandial hyperinsulinaemia 14 . Consistent with a minor role for direct hepatic effects of insulin, rodent models with altered hepatic insulin signalling exhibit relatively normal glucose tolerance and compensatory hyperinsulinaemia, with reduced hepatic glycogen synthesis as the only indication of disrupted insulin signalling 14,43,44,45,46,47 .

Direct assessment of glycogen synthesis by 13 C magnetic resonance spectroscopy demonstrated lower rates of postprandial and insulin-regulated hepatic glycogen synthesis in people with T2D 38,39 . The higher half-maximal effective concentration and lower maximum effect of insulin on hepatic glycogen synthesis 39 indicate impaired IR activation with subsequent posttranslational modifications of the glycogen synthetic machinery and transcriptional regulation of glucokinase (Fig. 1b). Whereas other insulin effects, such as transcriptional DNL activation via sterol receptor enhancing binding protein-1c (SREBP1c), would be expected to be blunted, hepatic insulin resistance is generally associated with increased hepatic TAG and NAFLD. Accordingly, it has been proposed that only the FOXO1-dependent, but not the SREBP1c-dependent branch of insulin signalling, is defective, suggesting selective hepatic insulin resistance 48 . This hypothesis relies on the assumption that DNL is the major source of hepatic TAG and on experiments showing different roles of insulin receptor substrate (IRS)-1 and IRS-2, substrate-specific AKT phosphorylation or intrinsic pathway sensitivities to insulin. Conversely, NEFA re-esterification probably accounts for the majority of hepatic lipogenesis and very low-density lipoprotein (VLDL) secretion 49,50,51 . Decreased insulin-stimulated hepatic IR kinase activity suggests a common proximal abnormality in T2D 52 . Furthermore, DNL upregulation is not dependent exclusively on IR kinase activity, but can also occur through activation of carbohydrate receptor enhancing binding protein (ChREBP) 53 , mTORC1–SREBP1c 54 and fructose-stimulated pathways 55 (Fig. 1b). A recent study found that fatty acid esterification to TAG is mostly dependent on NEFA delivery to the liver and independent of hepatic insulin signalling 16 . This alternative hypothesis also explains the development of NAFLD through increased NEFA flux derived from increased lipolysis by insulin-resistant WAT.

In addition to caloric overload, macronutrients exert specific effects by modulating enteroendocrine secretion and, in turn, pancreatic islet and brain function before reaching the splanchnic bed to directly stimulate insulin secretion and entering the liver. Only around 33% of dietary carbohydrates enter the liver, and dietary fat is considered to amount to only 10–20% of the hepatic fatty acid pool 49 . Nevertheless, macronutrients can deliver substrates for the hepatic acetyl-CoA pool, which allosterically stimulates gluconeogenesis or activates nutrient-sensitive pathways (ChREBP, mTORC and SREBP) to collectively stimulate the transcriptional DNL program. Elevated hepatic acyl-CoA favours production of sn-1,2-DAG, sphingolipids and TAG. In obese humans with NAFLD, the sn-1,2-DAG–PKCε pathway tightly correlates with hepatic insulin resistance 56,57,58,59,60 , whereas ceramide–JUN N-terminal kinase (JNK) correlates more with hepatic oxidative stress and inflammation 58,61,62 (Fig. 1b). In this context, lowering cellular ceramide by ablating dihydroceramide desaturase 1 increased mitochondrial oxygen flux and improved steatosis and glucose metabolism in insulin-resistant mice 63 . Conversely, mitochondrial C16:0 ceramide, generated by overexpression of ceramide synthase 6 (CerS6), interacts with mitochondrial fission factor (MFF) to promote mitochondrial fragmentation, insulin resistance and steatosis 64 . Silencing of MFF prevented CerS6-dependent metabolic abnormalities despite elevated C16:0 ceramide. This suggests that the effects of ceramides on insulin-stimulated glucose metabolism might result indirectly from impaired mitochondrial function with lower fatty acid oxidation, giving rise to other metabolites, for example, sn-1,2-DAG or acetyl-CoA, rather than from direct ceramide interference with insulin signalling. Recent studies indicate a critical role of molecular compartmentation of sn-1,2-DAGs, specifically in the plasma membrane, in inducing nPKC translocation and insulin resistance. Mice treated with CGI-58 antisense oligonucleotide exhibit elevated hepatic TAG and DAG in lipid droplets, are protected from lipid-induced hepatic insulin resistance and show reductions in plasma membrane DAG and PKCε translocation 65 .

Alvarez-Hernandez et al. monitored the earliest diet-induced metabolic alterations by examining the effect of a single oral saturated fat load in healthy humans 66 . This study revealed that saturated fat simultaneously induces insulin resistance in liver, skeletal muscle and WAT, and is associated with 70% higher rates of hepatic gluconeogenesis and 20% lower rates of net hepatic glycogenolysis. Similar studies in mice found upregulated expression of toll-like receptor (TLR) and inflammatory pathways, which might contribute to progression of NAFLD, including non-alcoholic steatohepatitis (NASH) 66 . Of note, chronic overfeeding also increased levels of intestine-derived endotoxins promoting TLR4-induced cytokine release by Kupffer cells 67,68 . Other intestinal functions also affect glycaemia and diabetes risk: integrin β7-knockout mice, which lack natural small-intestinal intraepithelial T lymphocytes, are metabolically hyperactive and resistant to obesity and diabetes 69 . Finally, dietary habits may affect the gut microbiota, modulating intestinal metabolite release and insulin sensitivity 70 . Humans with T2D and NAFLD show distinct metagenomic signatures along with increased branched-chain amino acids 71,72 and decreased short-chain NEFA 73 , which may affect body weight and metabolism.

In summary, overnutrition and WAT dysfunction lead to increased WAT lipolysis, which promotes insulin-independent hepatic lipogenesis resulting in increased ectopic lipid deposition and increased hepatic gluconeogenesis owing to increased increased acetyl-CoA stimulation of pyruvate carboxylase as well as increased glycerol conversion to glucose. This mechanism obviates the previously reported need to invoke selective hepatic insulin resistance to explain the discordance of increased hepatic lipogenesis occurring simultaneously with increased gluconeogenesis 48 (Fig. 1b). This is in line with recent studies showing that weight loss caused by very-low caloric diets rapidly normalizes hepatic steatosis and insulin resistance in liver, but not intramyocellular lipid content or muscle insulin resistance in individuals with T2D 3,11,74 .


The earliest land plants evolved from aquatic plants around 450 million years ago (Ma) in the Ordovician period. Many plants have adapted to iodine-deficient terrestrial environment by removing iodine from their metabolism, in fact iodine is essential only for animal cells. [2] An important antiparasitic action is caused by the block of the transport of iodide of animal cells inhibiting sodium-iodide symporter (NIS). Many plant pesticides are glycosides (as the cardiac digitoxin) and cyanogenic glycosides which liberate cyanide, which, blocking cytochrome c oxidase and NIS, is poisonous only for a large part of parasites and herbivores and not for the plant cells in which it seems useful in seed dormancy phase. Iodide is not a pesticide, but is oxidized, by vegetable peroxidase, to iodine, which is a strong oxidant, able to kill bacteria, fungi and protozoa. [3]

The Cretaceous period saw the appearance of more plant defense mechanisms. The diversification of flowering plants (angiosperms) at that time is associated with the sudden burst of speciation in insects. [4] This diversification of insects represented a major selective force in plant evolution, and led to selection of plants that had defensive adaptations. Early insect herbivores were mandibulate and bit or chewed vegetation but the evolution of vascular plants lead to the co-evolution of other forms of herbivory, such as sap-sucking, leaf mining, gall forming and nectar-feeding. [5]

The relative abundance of different species of plants in ecological communities including forests and grasslands may be determined in part by the level of defensive compounds in the different species. [6] Since the cost of replacement of damaged leaves is higher in conditions where resources are scarce, it may also be that plants growing in areas where water and nutrients are scarce may invest more resources into anti-herbivore defenses.

Records of herbivores Edit

Our understanding of herbivory in geological time comes from three sources: fossilized plants, which may preserve evidence of defense (such as spines), or herbivory-related damage the observation of plant debris in fossilised animal feces and the construction of herbivore mouthparts. [7]

Long thought to be a Mesozoic phenomenon, evidence for herbivory is found almost as soon as fossils which could show it. As previously discussed, the first land plants emerged around 450 million years ago however, herbivory, and therefore the need for plant defenses, has undoubtedly been around for longer. Herbivory first evolved due to marine organisms within ancient lakes and oceans. [8] Within under 20 million years of the first fossils of sporangia and stems towards the close of the Silurian, around 420 million years ago , there is evidence that they were being consumed. [9] Animals fed on the spores of early Devonian plants, and the Rhynie chert also provides evidence that organisms fed on plants using a "pierce and suck" technique. [7] Many plants of this time are preserved with spine-like enations, which may have performed a defensive role before being co-opted to develop into leaves.

During the ensuing 75 million years, plants evolved a range of more complex organs – from roots to seeds. There was a gap of 50 to 100 million years between each organ evolving, and it being fed upon. [9] Hole feeding and skeletonization are recorded in the early Permian, with surface fluid feeding evolving by the end of that period. [7]

Co-evolution Edit

Herbivores are dependent on plants for food, and have evolved mechanisms to obtain this food despite the evolution of a diverse arsenal of plant defenses. Herbivore adaptations to plant defense have been likened to offensive traits and consist of adaptations that allow increased feeding and use of a host plant. [10] Relationships between herbivores and their host plants often results in reciprocal evolutionary change, called co-evolution. When an herbivore eats a plant it selects for plants that can mount a defensive response. In cases where this relationship demonstrates specificity (the evolution of each trait is due to the other), and reciprocity (both traits must evolve), the species are thought to have co-evolved. [11]

The "escape and radiation" mechanism for co-evolution presents the idea that adaptations in herbivores and their host plants have been the driving force behind speciation, [4] [12] and have played a role in the radiation of insect species during the age of angiosperms. [13] Some herbivores have evolved ways to hijack plant defenses to their own benefit, by sequestering these chemicals and using them to protect themselves from predators. [4] Plant defenses against herbivores are generally not complete so plants also tend to evolve some tolerance to herbivory.

Plant defenses can be classified generally as constitutive or induced. Constitutive defenses are always present in the plant, while induced defenses are produced or mobilized to the site where a plant is injured. There is wide variation in the composition and concentration of constitutive defenses and these range from mechanical defenses to digestibility reducers and toxins. Many external mechanical defenses and large quantitative defenses are constitutive, as they require large amounts of resources to produce and are difficult to mobilize. [14] A variety of molecular and biochemical approaches are used to determine the mechanism of constitutive and induced plant defenses responses against herbivory. [15] [16] [17] [18]

Induced defenses include secondary metabolites, as well as morphological and physiological changes. [19] An advantage of inducible, as opposed to constitutive defenses, is that they are only produced when needed, and are therefore potentially less costly, especially when herbivory is variable. [19] Modes of induced defence include systemic acquired resistance [20] and plant-induced systemic resistance. [21]

Chemical defenses Edit

The evolution of chemical defenses in plants is linked to the emergence of chemical substances that are not involved in the essential photosynthetic and metabolic activities. These substances, secondary metabolites, are organic compounds that are not directly involved in the normal growth, development or reproduction of organisms, [22] and often produced as by-products during the synthesis of primary metabolic products. [23] Although these secondary metabolites have been thought to play a major role in defenses against herbivores, [4] [22] [24] a meta-analysis of recent relevant studies has suggested that they have either a more minimal (when compared to other non-secondary metabolites, such as primary chemistry and physiology) or more complex involvement in defense. [25] Furthermore, plants can release volatile organic compounds (VOCs) to warn other plants in the area of stressful conditions. These toxic compounds can be used to deter the herbivore or even attract the herbivore's predator.

Qualitative and quantitative metabolites Edit

Secondary metabolites are often characterized as either qualitative or quantitative. Qualitative metabolites are defined as toxins that interfere with a herbivore's metabolism, often by blocking specific biochemical reactions. Qualitative chemicals are present in plants in relatively low concentrations (often less than 2% dry weight), and are not dosage dependent. [ citation needed ] They are usually small, water-soluble molecules, and therefore can be rapidly synthesized, transported and stored with relatively little energy cost to the plant. Qualitative allelochemicals are usually effective against non-adapted generalist herbivores.

Quantitative chemicals are those that are present in high concentration in plants (5 – 40% dry weight) and are equally effective against all specialists and generalist herbivores. Most quantitative metabolites are digestibility reducers that make plant cell walls indigestible to animals. The effects of quantitative metabolites are dosage dependent and the higher these chemicals’ proportion in the herbivore's diet, the less nutrition the herbivore can gain from ingesting plant tissues. Because they are typically large molecules, these defenses are energetically expensive to produce and maintain, and often take longer to synthesize and transport. [26]

The geranium, for example, produces the amino acid, quisqualic acid in its petals to defend itself from Japanese beetles. Within 30 minutes of ingestion the chemical paralyzes the herbivore. While the chemical usually wears off within a few hours, during this time the beetle is often consumed by its own predators. [27] [28]

Antiherbivory compounds Edit

Plants have evolved many secondary metabolites involved in plant defense, which are collectively known as antiherbivory compounds and can be classified into three sub-groups: nitrogen compounds (including alkaloids, cyanogenic glycosides, glucosinolates and benzoxazinoids), terpenoids, and phenolics. [29]

Alkaloids are derived from various amino acids. Over 3000 known alkaloids exist, examples include nicotine, caffeine, morphine, cocaine, colchicine, ergolines, strychnine, and quinine. [30] Alkaloids have pharmacological effects on humans and other animals. Some alkaloids can inhibit or activate enzymes, or alter carbohydrate and fat storage by inhibiting the formation phosphodiester bonds involved in their breakdown. [31] Certain alkaloids bind to nucleic acids and can inhibit synthesis of proteins and affect DNA repair mechanisms. Alkaloids can also affect cell membrane and cytoskeletal structure causing the cells to weaken, collapse, or leak, and can affect nerve transmission. [32] Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly invoke an aversively bitter taste. [33]

Cyanogenic glycosides are stored in inactive forms in plant vacuoles. They become toxic when herbivores eat the plant and break cell membranes allowing the glycosides to come into contact with enzymes in the cytoplasm releasing hydrogen cyanide which blocks cellular respiration. [34] Glucosinolates are activated in much the same way as cyanogenic glucosides, and the products can cause gastroenteritis, salivation, diarrhea, and irritation of the mouth. [33] Benzoxazinoids, such as DIMBOA, are secondary defence metabolites characteristic of certain grasses (Poaceae). Like cyanogenic glycosides, they are stored as inactive glucosides in the plant vacuole. [35] Upon tissue disruption they get into contact with β-glucosidases from the chloroplasts, which enzymatically release the toxic aglucones. Whereas some benzoxazinoids are constitutively present, others are only synthesised following herbivore infestation, and thus, considered inducible plant defenses against herbivory. [36]

The terpenoids, sometimes referred to as isoprenoids, are organic chemicals similar to terpenes, derived from five-carbon isoprene units. There are over 10,000 known types of terpenoids. [37] Most are multicyclic structures which differ from one another in both functional groups, and in basic carbon skeletons. [38] Monoterpenoids, continuing 2 isoprene units, are volatile essential oils such as citronella, limonene, menthol, camphor, and pinene. Diterpenoids, 4 isoprene units, are widely distributed in latex and resins, and can be quite toxic. Diterpenes are responsible for making Rhododendron leaves poisonous. Plant steroids and sterols are also produced from terpenoid precursors, including vitamin D, glycosides (such as digitalis) and saponins (which lyse red blood cells of herbivores). [39]

Phenolics, sometimes called phenols, consist of an aromatic 6-carbon ring bonded to a hydroxy group. Some phenols have antiseptic properties, while others disrupt endocrine activity. Phenolics range from simple tannins to the more complex flavonoids that give plants much of their red, blue, yellow, and white pigments. Complex phenolics called polyphenols are capable of producing many different types of effects on humans, including antioxidant properties. Some examples of phenolics used for defense in plants are: lignin, silymarin and cannabinoids. [40] Condensed tannins, polymers composed of 2 to 50 (or more) flavonoid molecules, inhibit herbivore digestion by binding to consumed plant proteins and making them more difficult for animals to digest, and by interfering with protein absorption and digestive enzymes. [41]

In addition, some plants use fatty acid derivatives, amino acids and even peptides [42] as defenses. The cholinergic toxin, cicutoxin of water hemlock, is a polyyne derived from the fatty acid metabolism. [43] Oxalyldiaminopropionic acid is a neurotoxic amino acid produced as a defensive metabolite in the grass pea (Lathyrus sativus). [44] The synthesis of fluoroacetate in several plants is an example of the use of small molecules to disrupt the metabolism of herbivores, in this case the citric acid cycle. [45]

Mechanical defenses Edit

Many plants have external structural defenses that discourage herbivory. Structural defenses can be described as morphological or physical traits that give the plant a fitness advantage by deterring herbivores from feeding. [46] Depending on the herbivore's physical characteristics (i.e. size and defensive armor), plant structural defenses on stems and leaves can deter, injure, or kill the grazer. Some defensive compounds are produced internally but are released onto the plant's surface for example, resins, lignins, silica, and wax cover the epidermis of terrestrial plants and alter the texture of the plant tissue. The leaves of holly plants, for instance, are very smooth and slippery making feeding difficult. Some plants produce gummosis or sap that traps insects. [47]

Spines and thorns Edit

A plant's leaves and stem may be covered with sharp prickles, spines, thorns, or trichomes- hairs on the leaf often with barbs, sometimes containing irritants or poisons. Plant structural features like spines and thorns reduce feeding by large ungulate herbivores (e.g. kudu, impala, and goats) by restricting the herbivores' feeding rate, or by wearing down the molars. [48] Trichomes are frequently associated with lower rates of plant tissue digestion by insect herbivores. [46] Raphides are sharp needles of calcium oxalate or calcium carbonate in plant tissues, making ingestion painful, damaging a herbivore's mouth and gullet and causing more efficient delivery of the plant's toxins. The structure of a plant, its branching and leaf arrangement may also be evolved to reduce herbivore impact. The shrubs of New Zealand have evolved special wide branching adaptations believed to be a response to browsing birds such as the moas. [49] Similarly, African Acacias have long spines low in the canopy, but very short spines high in the canopy, which is comparatively safe from herbivores such as giraffes. [50] [51]

Trees such as palms protect their fruit by multiple layers of armor, needing efficient tools to break through to the seed contents. Some plants, notably the grasses, use indigestible silica (and many plants use other relatively indigestible materials such as lignin) to defend themselves against vertebrate and invertebrate herbivores. [52] Plants take up silicon from the soil and deposit it in their tissues in the form of solid silica phytoliths. These mechanically reduce the digestibility of plant tissue, causing rapid wear to vertebrate teeth and insect mandibles, [53] and are effective against herbivores above and below ground. [54] The mechanism may offer future sustainable pest control strategies. [55]

Thigmonastic movements Edit

Thigmonastic movements, those that occur in response to touch, are used as a defense in some plants. The leaves of the sensitive plant, Mimosa pudica, close up rapidly in response to direct touch, vibration, or even electrical and thermal stimuli. The proximate cause of this mechanical response is an abrupt change in the turgor pressure in the pulvini at the base of leaves resulting from osmotic phenomena. This is then spread via both electrical and chemical means through the plant only a single leaflet need be disturbed. This response lowers the surface area available to herbivores, which are presented with the underside of each leaflet, and results in a wilted appearance. It may also physically dislodge small herbivores, such as insects. [56]

Mimicry and camouflage Edit

Some plants mimic the presence of insect eggs on their leaves, dissuading insect species from laying their eggs there. Because female butterflies are less likely to lay their eggs on plants that already have butterfly eggs, some species of neotropical vines of the genus Passiflora (Passion flowers) contain physical structures resembling the yellow eggs of Heliconius butterflies on their leaves, which discourage oviposition by butterflies. [57]

Indirect defenses Edit

Another category of plant defenses are those features that indirectly protect the plant by enhancing the probability of attracting the natural enemies of herbivores. Such an arrangement is known as mutualism, in this case of the "enemy of my enemy" variety. One such feature are semiochemicals, given off by plants. Semiochemicals are a group of volatile organic compounds involved in interactions between organisms. One group of semiochemicals are allelochemicals consisting of allomones, which play a defensive role in interspecies communication, and kairomones, which are used by members of higher trophic levels to locate food sources. When a plant is attacked it releases allelochemics containing an abnormal ratio of these herbivore-induced plant volatiles (HIPVs). [58] [59] Predators sense these volatiles as food cues, attracting them to the damaged plant, and to feeding herbivores. The subsequent reduction in the number of herbivores confers a fitness benefit to the plant and demonstrates the indirect defensive capabilities of semiochemicals. [60] Induced volatiles also have drawbacks, however some studies have suggested that these volatiles attract herbivores. [58]

Plants sometimes provide housing and food items for natural enemies of herbivores, known as "biotic" defense mechanisms, as a means to maintain their presence. For example, trees from the genus Macaranga have adapted their thin stem walls to create ideal housing for an ant species (genus Crematogaster), which, in turn, protects the plant from herbivores. [61] In addition to providing housing, the plant also provides the ant with its exclusive food source from the food bodies produced by the plant. Similarly, several Acacia tree species have developed stipular spines (direct defenses) that are swollen at the base, forming a hollow structure that provides housing for protective ants. These Acacia trees also produce nectar in extrafloral nectaries on their leaves as food for the ants. [62]

Plant use of endophytic fungi in defense is common. Most plants have endophytes, microbial organisms that live within them. While some cause disease, others protect plants from herbivores and pathogenic microbes. Endophytes can help the plant by producing toxins harmful to other organisms that would attack the plant, such as alkaloid producing fungi which are common in grasses such as tall fescue (Festuca arundinacea). [56]

Leaf shedding and color Edit

There have been suggestions that leaf shedding may be a response that provides protection against diseases and certain kinds of pests such as leaf miners and gall forming insects. [63] Other responses such as the change of leaf colors prior to fall have also been suggested as adaptations that may help undermine the camouflage of herbivores. [64] Autumn leaf color has also been suggested to act as an honest warning signal of defensive commitment towards insect pests that migrate to the trees in autumn. [65] [66]

Defensive structures and chemicals are costly as they require resources that could otherwise be used by plants to maximize growth and reproduction. Many models have been proposed to explore how and why some plants make this investment in defenses against herbivores.

Optimal defense hypothesis Edit

The optimal defense hypothesis attempts to explain how the kinds of defenses a particular plant might use reflect the threats each individual plant faces. [67] This model considers three main factors, namely: risk of attack, value of the plant part, and the cost of defense. [68] [69]

The first factor determining optimal defense is risk: how likely is it that a plant or certain plant parts will be attacked? This is also related to the plant apparency hypothesis, which states that a plant will invest heavily in broadly effective defenses when the plant is easily found by herbivores. [70] Examples of apparent plants that produce generalized protections include long-living trees, shrubs, and perennial grasses. [70] Unapparent plants, such as short-lived plants of early successional stages, on the other hand, preferentially invest in small amounts of qualitative toxins that are effective against all but the most specialized herbivores. [70]

The second factor is the value of protection: would the plant be less able to survive and reproduce after removal of part of its structure by a herbivore? Not all plant parts are of equal evolutionary value, thus valuable parts contain more defenses. A plant's stage of development at the time of feeding also affects the resulting change in fitness. Experimentally, the fitness value of a plant structure is determined by removing that part of the plant and observing the effect. [71] In general, reproductive parts are not as easily replaced as vegetative parts, terminal leaves have greater value than basal leaves, and the loss of plant parts mid-season has a greater negative effect on fitness than removal at the beginning or end of the season. [72] [73] Seeds in particular tend to be very well protected. For example, the seeds of many edible fruits and nuts contain cyanogenic glycosides such as amygdalin. This results from the need to balance the effort needed to make the fruit attractive to animal dispersers while ensuring that the seeds are not destroyed by the animal. [74] [75]

The final consideration is cost: how much will a particular defensive strategy cost a plant in energy and materials? This is particularly important, as energy spent on defense cannot be used for other functions, such as reproduction and growth. The optimal defense hypothesis predicts that plants will allocate more energy towards defense when the benefits of protection outweigh the costs, specifically in situations where there is high herbivore pressure. [76]

Carbon:nutrient balance hypothesis Edit

The carbon:nutrient balance hypothesis, also known as the environmental constraint hypothesis or Carbon Nutrient Balance Model (CNBM), states that the various types of plant defenses are responses to variations in the levels of nutrients in the environment. [77] [78] This hypothesis predicts the Carbon/Nitrogen ratio in plants determines which secondary metabolites will be synthesized. For example, plants growing in nitrogen-poor soils will use carbon-based defenses (mostly digestibility reducers), while those growing in low-carbon environments (such as shady conditions) are more likely to produce nitrogen-based toxins. The hypothesis further predicts that plants can change their defenses in response to changes in nutrients. For example, if plants are grown in low-nitrogen conditions, then these plants will implement a defensive strategy composed of constitutive carbon-based defenses. If nutrient levels subsequently increase, by for example the addition of fertilizers, these carbon-based defenses will decrease.

Growth rate hypothesis Edit

The growth rate hypothesis, also known as the resource availability hypothesis, states that defense strategies are determined by the inherent growth rate of the plant, which is in turn determined by the resources available to the plant. A major assumption is that available resources are the limiting factor in determining the maximum growth rate of a plant species. This model predicts that the level of defense investment will increase as the potential of growth decreases. [79] Additionally, plants in resource-poor areas, with inherently slow-growth rates, tend to have long-lived leaves and twigs, and the loss of plant appendages may result in a loss of scarce and valuable nutrients. [80]

One test of this model involved a reciprocal transplants of seedlings of 20 species of trees between clay soils (nutrient rich) and white sand (nutrient poor) to determine whether trade-offs between growth rate and defenses restrict species to one habitat. When planted in white sand and protected from herbivores, seedlings originating from clay outgrew those originating from the nutrient-poor sand, but in the presence of herbivores the seedlings originating from white sand performed better, likely due to their higher levels of constitutive carbon-based defenses. These finding suggest that defensive strategies limit the habitats of some plants. [81]

Growth-differentiation balance hypothesis Edit

The growth-differentiation balance hypothesis states that plant defenses are a result of a tradeoff between "growth-related processes" and "differentiation-related processes" in different environments. [82] Differentiation-related processes are defined as "processes that enhance the structure or function of existing cells (i.e. maturation and specialization)." [67] A plant will produce chemical defenses only when energy is available from photosynthesis, and plants with the highest concentrations of secondary metabolites are the ones with an intermediate level of available resources. [82]

The GDBH also accounts for tradeoffs between growth and defense over a resource availability gradient. In situations where resources (e.g. water and nutrients) limit photosynthesis, carbon supply is predicted to limit both growth and defense. As resource availability increases, the requirements needed to support photosynthesis are met, allowing for accumulation of carbohydrate in tissues. As resources are not sufficient to meet the large demands of growth, these carbon compounds can instead be partitioned into the synthesis of carbon based secondary metabolites (phenolics, tannins, etc.). In environments where the resource demands for growth are met, carbon is allocated to rapidly dividing meristems (high sink strength) at the expense of secondary metabolism. Thus rapidly growing plants are predicted to contain lower levels of secondary metabolites and vice versa. In addition, the tradeoff predicted by the GDBH may change over time, as evidenced by a recent study on Salix spp. Much support for this hypothesis is present in the literature, and some scientists consider the GDBH the most mature of the plant defense hypotheses. [ citation needed ] [ opinion ]

Agriculture Edit

The variation of plant susceptibility to pests was probably known even in the early stages of agriculture in humans. In historic times, the observation of such variations in susceptibility have provided solutions for major socio-economic problems. The hemipteran pest insect phylloxera was introduced from North America to France in 1860 and in 25 years it destroyed nearly a third (100,000 km 2 ) of French vineyards. Charles Valentine Riley noted that the American species Vitis labrusca was resistant to Phylloxera. Riley, with J. E. Planchon, helped save the French wine industry by suggesting the grafting of the susceptible but high quality grapes onto Vitis labrusca root stocks. [83] The formal study of plant resistance to herbivory was first covered extensively in 1951 by Reginald Henry Painter, who is widely regarded as the founder of this area of research, in his book Plant Resistance to Insects. [84] While this work pioneered further research in the US, the work of Chesnokov was the basis of further research in the USSR. [85]

Fresh growth of grass is sometimes high in prussic acid content and can cause poisoning of grazing livestock. The production of cyanogenic chemicals in grasses is primarily a defense against herbivores. [86] [87]

The human innovation of cooking may have been particularly helpful in overcoming many of the defensive chemicals of plants. Many enzyme inhibitors in cereal grains and pulses, such as trypsin inhibitors prevalent in pulse crops, are denatured by cooking, making them digestible. [88] [89]

It has been known since the late 17th century that plants contain noxious chemicals which are avoided by insects. These chemicals have been used by man as early insecticides in 1690 nicotine was extracted from tobacco and used as a contact insecticide. In 1773, insect infested plants were treated with nicotine fumigation by heating tobacco and blowing the smoke over the plants. [90] The flowers of Chrysanthemum species contain pyrethrin which is a potent insecticide. In later years, the applications of plant resistance became an important area of research in agriculture and plant breeding, particularly because they can serve as a safe and low-cost alternative to the use of pesticides. [91] The important role of secondary plant substances in plant defense was described in the late 1950s by Vincent Dethier and G.S. Fraenkel. [22] [92] The use of botanical pesticides is widespread and notable examples include Azadirachtin from the neem (Azadirachta indica), d-Limonene from Citrus species, Rotenone from Derris, Capsaicin from chili pepper and Pyrethrum. [93]

Natural materials found in the environment also induce plant resistance as well. [94] Chitosan derived from chitin induce a plant's natural defense response against pathogens, diseases and insects including cyst nematodes, both are approved as biopesticides by the EPA to reduce the dependence on toxic pesticides.

The selective breeding of crop plants often involves selection against the plant's intrinsic resistance strategies. This makes crop plant varieties particularly susceptible to pests unlike their wild relatives. In breeding for host-plant resistance, it is often the wild relatives that provide the source of resistance genes. These genes are incorporated using conventional approaches to plant breeding, but have also been augmented by recombinant techniques, which allow introduction of genes from completely unrelated organisms. The most famous transgenic approach is the introduction of genes from the bacterial species, Bacillus thuringiensis, into plants. The bacterium produces proteins that, when ingested, kill lepidopteran caterpillars. The gene encoding for these highly toxic proteins, when introduced into the host plant genome, confers resistance against caterpillars, when the same toxic proteins are produced within the plant. This approach is controversial, however, due to the possibility of ecological and toxicological side effects. [95]

Pharmaceutical Edit

Many currently available pharmaceuticals are derived from the secondary metabolites plants use to protect themselves from herbivores, including opium, aspirin, cocaine, and atropine. [96] These chemicals have evolved to affect the biochemistry of insects in very specific ways. However, many of these biochemical pathways are conserved in vertebrates, including humans, and the chemicals act on human biochemistry in ways similar to that of insects. It has therefore been suggested that the study of plant-insect interactions may help in bioprospecting. [97]

There is evidence that humans began using plant alkaloids in medical preparations as early as 3000 B.C. [31] Although the active components of most medicinal plants have been isolated only recently (beginning in the early 19th century) these substances have been used as drugs throughout the human history in potions, medicines, teas and as poisons. For example, to combat herbivory by the larvae of some Lepidoptera species, Cinchona trees produce a variety of alkaloids, the most familiar of which is quinine. Quinine is extremely bitter, making the bark of the tree quite unpalatable. It is also an anti-fever agent, known as Jesuit's bark, and is especially useful in treating malaria. [98]

Throughout history mandrakes (Mandragora officinarum) have been highly sought after for their reputed aphrodisiac properties. However, the roots of the mandrake plant also contain large quantities of the alkaloid scopolamine, which, at high doses, acts as a central nervous system depressant, and makes the plant highly toxic to herbivores. Scopolamine was later found to be medicinally used for pain management prior to and during labor in smaller doses it is used to prevent motion sickness. [99] One of the most well-known medicinally valuable terpenes is an anticancer drug, taxol, isolated from the bark of the Pacific yew, Taxus brevifolia, in the early 1960s. [100]

Biological pest control Edit

Repellent companion planting, defensive live fencing hedges, and "obstructive-repellent" interplanting, with host-plant resistance species as beneficial 'biological control agents' is a technique in biological pest control programs for: organic gardening, wildlife gardening, sustainable gardening, and sustainable landscaping in organic farming and sustainable agriculture and in restoration ecology methods for habitat restoration projects.

Cancer Drug Resistance: Unraveling Its Complexity

It’s a heartbreaking story, and one that happens too often. A patient with advanced cancer receives a drug that helps shrink their tumors, allowing them more time with family, but then weeks or months later the cancer comes back and the drug no longer works.

Drug resistance remains one of the biggest challenges in cancer therapy. It exists across all types of cancer and all modes of treatment, including molecularly targeted therapy, immunotherapy, and chemotherapy. Solving the puzzle of why cancers become resistant to therapy and how to overcome or prevent it is a goal that NCI is pursuing on many fronts, including basic science to understand biological mechanisms and clinical trials testing new treatment strategies.

Multiple factors, within cancer cells themselves and in the local environment in which the cancer cells exist (the tumor microenvironment), contribute to how well a drug works. These factors may differ from patient to patient and even among tumors in a single patient. Tumors are made of diverse cells that may have different genetic, epigenetic, and metabolic characteristics that have different sensitivities to treatment. Tumors also consist of immune cells, blood vessels, fibroblasts, and other cells and components that interact with the cancer cells. These interactions often promote tumor development, progression, and response to treatment.

Having Faith in Science to Treat Prostate Cancer

Although a drug may kill some cancer cells, almost invariably a subset of them will be resistant and survive the treatment. Cancers often have multiple mechanisms for surviving and growing, which may change over time and in response to treatment. That is why combining treatments that have different mechanisms of action can kill more cancer cells and reduce the chance that drug resistance will emerge.

Most of the research on drug resistance has focused on identifying genetic mechanisms, such as mutations that alter a protein such that it impairs the binding of a drug. Research is revealing the importance of additional mechanisms of drug resistance, such as epigenetic factors that regulate the activity of genes and the dynamics between diverse cells in the tumor microenvironment. Overcoming resistance, then, requires understanding these complex biological processes in the first place, to better anticipate and steer the dynamic, multidimensional evolutionary process unfolding inside a patient with cancer.

Aided by advanced preclinical tools and new drug design approaches, NCI-funded researchers are revealing a clearer picture of cancer drug resistance and developing new treatment approaches to overcome it.

Targeting Cancer Cell Plasticity

Starting in 2006, doctors began to describe rare cases of patients with non-small cell lung cancer (NSCLC) whose cancers transformed into small cell lung cancer after treatment with EGFR inhibitors. This change in cell identity is one type of what scientists refer to as cell plasticity, and NCI-funded research is piecing together the puzzle of how it may hinder cancer treatment.

Cell plasticity is a cell’s ability to undergo changes that alter its appearance and function (its phenotype). These changes can occur in cancer cells because of genetic and nongenetic alterations, cues from other cells in the tumor microenvironment, and/or drug treatment. A cell’s ability to change and adapt offers it additional routes to resist treatment.

More recently, similar observations emerged from men with prostate cancer who were treated with androgen deprivation therapy: aggressive and deadly forms of neuroendocrine prostate cancers emerged. In addition to NSCLC and prostate cancer, scientists have described cell plasticity in several additional cancer types, including melanoma and breast cancer.

While different cancers demonstrate their own patterns of cell plasticity, NCI-funded research has revealed some biological mechanisms that are common across cancer types. For example, research supported by NCI has implicated EZH2, an enzyme that regulates gene expression, in the ability of both NSCLC and prostate cancer to change phenotypes. Thus, research on one cancer may enrich studies of resistance patterns in other cancers, resulting in the identification of treatments that could work for several cancer types. This example illustrates that our understanding of the fundamental and molecular mechanisms of cancer is fueling advances in precision oncology, including drugs approved to treat cancers with specific genetic abnormalities rather than where in the body the cancer started.

Treating Cancers Like Evolving Ecosystems

A tumor can be thought of as an ecological system that evolves over time. Researchers are therefore applying the concepts of evolutionary ecology to study cancer and its response to treatment. Evolutionary ecology is a scientific field that examines how interactions among species and between species and their environment shape species through selection and adaptation, and the consequences of the resulting evolutionary change.

As an example, NCI-funded research led by investigators at Cleveland Clinic and Case Comprehensive Cancer Center recently developed an "evolutionary game assay" that directly quantifies and describes the interactions between tumor cells that are sensitive and resistant to a targeted therapy in an experimental model of NSCLC. They found that the interactions between cells were different under different conditions. The researchers suggest that changing the types of interactions between cells—in other words, the "games they play"—can co-opt the cells’ evolution to better help the patient by preventing drug-resistant cells from “winning.”

Other NCI-funded studies are testing whether different drug doses and schedules might decrease the likelihood that drug resistance will develop as a result of evolutionary dynamics. For example, if drugs can be given in a way that allows a proportion of the easier-to-treat sensitive cells to disproportionately survive, they may compete with and block the growth of the resistant cells in the tumor. With this adaptive cancer therapy approach, it is possible that the tumor may never be completely eradicated, but it may remain relatively stable, thereby limiting the development of uncontrollable drug resistance.

Degrading—Not Blocking—the Target to Avoid Resistance

Using new technology to degrade proteins of interest, such as those that drive cancer cell growth, is an emerging cancer treatment strategy. One example of this technology is called proteolysis targeting chimera (PROTAC), in which molecules are generated that tag a specific protein for degradation by a cell’s normal machinery for getting rid of unwanted or damaged proteins. An advantage of this approach is that it can avoid some mechanisms of drug resistance seen with some cancer therapies, such as mutations in the target of a drug or overexpression of the target.

For example, NCI-funded researchers at Yale University created a PROTAC molecule as a potential treatment for advanced prostate cancer. Androgen receptor (AR) signaling plays a pivotal role in prostate cancer initiation and growth, and drugs that inhibit ARs are the standard of care for patients with metastatic disease. Unfortunately, most tumors treated with AR inhibitors eventually develop drug resistance. Some mechanisms of resistance result in continued AR signaling despite the presence of these drugs.

The PROTAC molecule the Yale team invented consists of an AR-targeting portion and a portion that binds selectively to a protein, called E3 ligase. The E3 ligase is part of the cell’s normal machinery that degrades proteins. With additional support from NCI’s Small Business Innovation Research (SBIR) program, Arvinas, Inc. of New Haven, Connecticut, is further developing and testing this PROTAC in clinical trials for patients with metastatic prostate cancer whose cancer has progressed after AR therapy.

With the help of NCI funding, PROTAC and other similar technologies have shown promise in addressing resistance in other cancer types, including chronic lymphocytic leukemia that has become resistant to the drug ibrutinib (Imbruvica).

Using Advanced Preclinical Models to Address Resistance

Researchers have traditionally used cancer cell lines to study mutations and other mechanisms that make cancer cells sensitive or resistant to therapies. But cell lines do not always share key features of cancers found in patients. In addition, cancer cell lines lack the three-dimensional structure of a tumor found in a person and the relationships with surrounding cells in the tumor microenvironment.

Animal models, such as mice that carry tumors implanted from a sample of a patient’s cancer, can more closely resemble the tumors found in humans. The tumor microenvironment and cancer growth, progression, and treatment effects of animal models more closely mimic those found in people. However, animal models are expensive, can take months to produce, and are not made in large enough quantities for testing more than a few drugs at a time. They also lack an intact immune system, making them inadequate to study the interaction between the immune system and cancer. While current cancer models are useful for answering some research questions, additional tools are needed.

NCI-funded researchers are leveraging new technologies and models to gain a fuller understanding of drug resistance. They include three-dimensional human tumor cultures and engineered platforms that support living human tissues, both of which incorporate cells that surround and interact with tumor cells in the tumor microenvironment to mimic conditions in the human body.

Miniature tumors called patient-derived tumor organoids are three-dimensional cancer cell clusters grown in the lab from a sample of a patient’s tumor. Scientists are using them in the laboratory to study various aspects of cancer biology, including mechanisms of drug resistance. Researchers have developed organoids from a variety of cancer types, including breast, prostate, liver, brain, and pancreatic cancer.

One example of this research is in pancreatic cancer, which is one of the most lethal cancer types, in part because it is largely resistant to treatment and is generally detected at a late stage after the cancer has spread. NCI-funded researchers at Cold Spring Harbor Laboratory in New York and their collaborators have created a “living library” of pancreatic cancer organoids derived from patient samples from multiple clinical institutions. In a retrospective analysis of a small number of patients, the organoid’s sensitivity to chemotherapy reflected the patient’s response to therapy. In addition, tumor sampling in a single patient over time predicted the development of chemotherapy resistance that paralleled disease progression in the patient. Understanding why resistance emerges and having models to help predict it could improve the selection of treatments for patients in the future.

Scientists are developing additional cancer models that accurately represent the structure and function of tumors in human organs and tissues. For example, tissue chips are three-dimensional cross sections of living human tissue on a device about the size of a computer memory stick. For cancer researchers, tissue chips and other engineered tumor systems are enhancing the understanding of tumor physiology and aiding cancer treatment research.

For example, NCI is funding research projects that are developing and using engineered tumor systems to study drug response and resistance in cancers of the brain, ovaries, and breast. In addition, NCI’s SBIR program has supported several companies developing cancer chips, including one developed by researchers at the University of Virginia and HemoShear Therapeutics, LLC of Charlottesville, Virginia, to assess drug sensitivity and resistance in pancreatic cancer.

Landmark TB Trial Identifies Shorter-Course Treatment Regimen

Results from an international, randomized, controlled clinical trial indicate that a four-month daily treatment regimen containing high-dose, or “optimized,” rifapentine with moxifloxacin is as safe and effective as the existing standard six-month daily regimen at curing drug-susceptible tuberculosis (TB) disease. This regimen is the first successful short-course treatment regimen for drug-susceptible TB disease in almost 40 years. TB is one of the most important global health problems. According to recent estimates from the World Health Organization, 10 million new TB cases and 1.4 million deaths from TB occurred globally in 2019. While the United States has achieved substantial progress in reducing TB, with fewer than 10,000 cases each year, too many people still suffer from TB disease.

The Phase 3, open-label trial, called Study 31/A5349, was led by the U.S. Centers for Disease Control and Prevention’s (CDC) Tuberculosis Trials Consortium (TBTC) with collaboration from the AIDS Clinical Trials Group (ACTG) funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. It is the largest drug-susceptible TB disease treatment trial that CDC or NIAID has ever conducted, with more than 2,500 participants ages 12 and older enrolled at 34 clinical sites in 13 countries. The trial included 214 people with HIV. Results were presented today at the virtual Union World Conference on Lung Health and have been submitted for publication.

Shortening treatment for TB disease can benefit patients, families, healthcare providers and health systems. Shorter TB disease treatment regimens can help patients more easily complete treatment for TB disease than they would on the existing standard regimen. This is especially important in the era of COVID-19, which has caused widespread disruptions to care and treatment access for many people with TB disease. The availability of shorter regimens enables patients to be cured faster, and has the potential to reduce treatment costs, improve patient quality of life, increase completion of therapy, and reduce development of drug resistance.

“The CDC’s TB Trials Consortium is a global leader in driving innovation and advances in TB treatment and prevention, such as this new four-month regimen,” said Philip LoBue, MD, FACP, FCCP, director of CDC’s Division of Tuberculosis Elimination. “These results help bring us closer to our goal of TB elimination, and we are grateful to the researchers, clinical staff, and most of all, study participants, for their important contributions.”

“These robust findings have the potential to change clinical practice by offering people with drug-susceptible TB an additional, shorter-course treatment option that is safe, effective and potentially more convenient,” said Carl W. Dieffenbach, PhD, director of the NIAID Division of AIDS. “The Study 31/A5349 trial was completed right on schedule, demonstrating the effectiveness of the collaboration between CDC and NIAID.”

Study 31/A5349 examined the efficacy and safety of two four-month regimens with high-dose rifapentine with or without moxifloxacin for the treatment of drug-susceptible TB disease. These were compared with the existing six-month regimen (2RHZE/4RH), which includes eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol and 18 weeks of daily treatment with rifampin and isoniazid.

One of the four-month regimens – 2PHZM/2PHM – included eight weeks of daily treatment with high-dose, or “optimized,” rifapentine, isoniazid, pyrazinamide, and moxifloxacin and nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin. At the conclusion of the trial, the four-month regimen met non-inferiority criteria for efficacy in all of the several planned analyses and was safe and well-tolerated.

A second new treatment regimen used in this study – 2PHZE/2PH – included eight weeks of daily treatment with the same dose of rifapentine, isoniazid, pyrazinamide, and ethambutol and nine weeks of daily treatment with rifapentine and isoniazid. This new regimen did not meet non-inferiority criteria when compared to the existing standard regimen.

The safety profile for this trial demonstrates that the proportion of patients who experienced adverse events was similar among patients in all three groups of participants (control and the two novel regimen groups). This means that the novel regimens do not pose greater risk to patients than currently used regimens.

Study 31/A5349 will inform future TB treatment in the U.S. CDC and NIH will continue to work with TB control programs and clinicians to improve available treatment and prevention regimens for TB disease.

Study 31/A5349 was presented today at the 51st Union World Conference on Lung Health, held virtually from October 20-24, 2020.

CDC’s Division of Tuberculosis Elimination Director, Philip LoBue, and NIAID’s Division of AIDS Director, Carl Dieffenbach, are available for comment on this study’s implications for the future of TB disease treatment.

On the Cover

The cover image is based on the Original Article entitled A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential by Junwei Gai et al., MedComm. 2021 2:101-113.

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