5 Must-Have Features in a Antibiotics Exporter

Drug repurposing, or identifying new uses for existing drugs, has emerged as an alternative to traditional drug discovery processes involving de novo synthesis. Drugs that are currently approved or under development for non-antibiotic indications may possess antibiotic properties, and therefore may have repurposing potential, either alone or in combination with an antibiotic. They might also serve as &#;antibiotic adjuvants&#; to enhance the activity of certain antibiotics.

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Traditional drug discovery strategies aim to identify the next new chemical or molecular entity that possesses a novel mechanism of action. For any promising new compound, the path from initial discovery to market launch is sluggish, costly, and fraught with a multitude of barriers. Moving a new drug from pre-clinical phases to market generally requires a minimum timeframe of 10-12 years and over $2 billion in resources ( DiMasi, ; DiMasi et al., ). Additionally, the probability of success is low, with only 1-2 drugs from an initial 10,000 compounds reaching Federal Drug Administration (FDA) approval. Following target identification and validation, high-throughput screening (HTS) assays are developed and run against compound libraries to generate &#;hits&#;, which are the compounds that demonstrate the desired activity or interaction with the target of interest. Each hit series undergoes additional screening and/or chemical modifications to become more &#;druggable&#; lead compounds before in vitro and in vivo pharmacokinetic testing is performed in animal models (preclinical). Generally, only a handful of drug candidates from the initial 10,000 compounds enter clinical trials. Success rates for drugs entering Phase I clinical trials have approximately 10% chance of gaining FDA approval for the desired indication ( Mullard, ).

Antibiotic Drug Development: A Historical Perspective

Milestones of antibiotic discovery and development can offer insights into future solutions. The pre-antibiotic era bears striking resemblance to circumstances of today, regarding a need for: 1) novel, effective antibiotics, 2) large scale collaboration, and 3) efficient processes/timelines for antibiotic approvals.

The Antibiotic Era

The drug discovery landscape was forever changed after the arrival of penicillin. Not only did it save thousands of lives, it also ushered in an era of natural products discovery (Wright, ; Moloney, ). Building on the work of Fleming, microbiologist Selman Waksman sought to find more sources of antibiotic-producing microbes from soil. His approach involved the screening of soil-derived bacteria (mostly Actinomycetes spp.) against susceptible test organisms and evaluating zones of inhibited growth on an overlay plate (Schatz et al., ). This method is similar to Fleming&#;s discovery of penicillin; however, Waksman applied a more systematic, deliberate screening approach, while Fleming&#;s discovery of an antibiotic-producing mold was accidental. This new screening approach, otherwise known as the &#;Waksman platform&#; led to the discovery of an important antibiotic streptomycin, which exhibited in vitro activity against Gram-positive and Gram-negative bacteria (Jones et al., ). Though penicillin was highly effective and in frequent use at the time, its antibacterial activity was primarily limited to Gram-positive bacteria. Streptomycin, the first of the aminoglycoside antibiotic class, was also the first drug with activity against Mycobacterium tuberculosis.

After the successful launch of streptomycin, the Waksman platform quickly became the quintessential tool for antibiotic discovery at the time, and ultimately the most successful and widely adopted antibiotic discovery platform to date. Discovery of other antibiotics occurred shortly thereafter, and continued over the next 20 years, famously referred to as the &#;golden age&#; of antibiotics (Lewis, ; Lyddiard et al., ). In fact, the bulk of antibiotics in use today are from natural products or their semisynthetic derivatives that were discovered by this method of mining through soil-derived compounds (Moloney, ; Mohr, ; Katz and Baltz, ). Vancomycin, clindamycin, rifampin, tetracycline, and daptomycin are among a few important natural product antibiotics discovered during this era that remain in use today ( Table 1 ).

Table 1.

Antibiotics derived from natural products (Lewis, ; Wright, ).

Antibiotic class Example of clinically used drugs Biological target β-lactam Penicillins: amoxicillin, ampicillin, piperacillin, cephalosporins: cephalexin, cefaclor, ceftazidime, Carbapenems: imipenem, meropenem Peptidoglycan synthesis; transpeptidases Glycopeptide Vancomycin Peptidoglycan synthesis; binding to acyl-D-Ala-D-Ala Macrolide Erythromycin, clarithromycin, azithromycin Ribosome; blocks peptide exit tunnel in the large subunit Lincosamide Clindamycin Ribosome; blocks peptide exit tunnel in the large subunit Aminoglycoside Gentamicin, tobramycin, amikacin Ribosome; impairs cognate aminoacyl-tRNA recognition Streptogramin Synercid (quinupristin + dalfopristin) Ribosome: inhibits peptidyl transfer, blocks peptide exit tunnel in large subunit Tetracycline Doxycycline, minocycline Ribosome: inhibits aminoacyl-tRNA transfer, blocks peptide exit tunnel in small subunit Rifamycin Rifampin RNA polymerase Lipopeptide Daptomycin Cell membrane Cationic peptide Colistin Cell membrane Open in a new tab

Emergence of Resistance

Antibiotic resistance is an extremely complicated problem. The urgency to develop new antibiotics is almost entirely driven by escalating resistance rates (Theuretzbacher, ). The first sign of penicillin resistance was observed in , several years before penicillin was available for widespread use (), when a penicillin-inactivating enzyme (penicillinase) was discovered in an E. coli strain (Abraham and Chain, ). In , penicillin resistance was noted in four clinical strains of S. aureus, also by a penicillinase (Rammelkamp and Stolzer, ). Unfortunately, this was only the beginning. As each new antibiotic was launched into market, reports of resistance followed shortly thereafter. Over time, this pattern began occurring in a variety of bacterial pathogens, spanning several decades. Today, there is no shortage of antibiotic resistant bacteria, but there is a shortage of effective treatment options.

Until better control measures are in place and more novel antibiotics are available, the threat of resistance will loom, putting an expiration date on each and every antibiotic in use.

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Several factors affect which antibiotics and how much of them are used in animal agriculture. Global and national regulations play an important role; but self&#;imposed limitations within the private sector are also meaningful factors.

WHO recommendations for antimicrobial use in agriculture

In , the WHO published four broad recommendations on the use of medically important antimicrobials in food animal production in order to maintain effectiveness of these antimicrobials in human medicine.3 To develop the basis for its recommendations, the WHO commissioned two independent systematic reviews, the first of which was published in Lancet Planetary Health in .1, 15 The review concluded that interventions aimed at reducing antibiotic use in food&#;producing animals were associated with reduced antibiotic resistance in these animals, but there was less compelling evidence that these interventions also reduced antibiotic resistance in human populations.

The first WHO recommendation calls for an &#;overall reduction in use of all classes of medically important antimicrobials in food&#;producing animals.&#; Similarly, the second recommendation calls for the &#;complete restriction of use of all classes of medically important antimicrobials in food&#;producing animals for growth promotion.&#; Those two recommendations were well received by experts in the food&#;animal industry, particularly in the United States, where the FDA had already achieved a de facto ban on the use of medically important antibiotics for growth promotion in through voluntary withdrawal of labels by drug sponsors.

By contrast, Recommendation 3&#;which calls for the &#;complete restriction of use of all classes of medically important antimicrobials in food&#;producing animals for prevention of infectious diseases that have not yet been clinically diagnosed&#;&#;has been rejected outright by many.16, 17 The main issue with this recommendation seems to be that there is no universally accepted definition of what is meant by prevention, as organizations each defines prevention in different ways and adds to the confusion. Nevertheless, on November 30, , a major U.S. poultry producer committed to achieving the equivalent of the third WHO Guideline recommendation by March by removing its use of gentamicin and virginiamycin from its prevention protocols.18

Recommendation 4 from the WHO, which is a two&#;part recommendation, is widely viewed as highly controversial.16, 19, 20 Recommendation 4a states that antimicrobials classified by WHO as &#;critically important for human medicine (&#;) should not be used for control of the dissemination of a clinically diagnosed infectious disease identified within a group of food&#;producing animals.&#; Recommendation 4b states that antimicrobials that are the &#;highest priority critically important for human medicine should not be used for treatment of food&#;producing animals with a clinically diagnosed infectious disease.&#; These latter two recommendations (4a and 4b) are supported by the lowest quality of evidence (per GRADE criteria) and are not strongly made by WHO (in contrast to Recommendation 3).21

The Chief Scientist of the U.S. Department of Agriculture (USDA) denounced these recommendations, stating they would &#;impose unnecessary and unrealistic constraints&#; on veterinarians&#; professional judgment to treat, control, and prevent disease.16 The USDA also condemned the recommendations for being unsupported by sound data and out of alignment with U.S. policy.16 Similarly, the American Veterinary Medical Association (AVMA) criticized the recommendations as putting &#;unwarranted restrictions&#; on antibiotic use for protecting animal health and the food supply.17

Both the USDA and AVMA pointed out that the WHO developed the recommendations based on evidence that was by the WHO's own assessment of &#;low&#;quality&#; (Recommendations 1&#;3) and &#;very low&#;quality&#; (Recommendations 4a and 4b). However, the systematic review on which the recommendations were primarily based could only analyze available observational studies (cross&#;sectional and longitudinal) that are by definition low quality according to the WHO grading system (GRADE). Some critics have suggested that the WHO change its grading system so that the types of studies needed here, which are not conducive to randomized trials, can be graded as being of higher quality. However, the philosophy at the WHO tends toward preemptive action, which leads to more cautious recommendations. Within this context, researchers are currently evaluating the grading system and the studies on which Recommendations 3 and 4 were based.

Clearly, there needs to be a more universally recognized definition of prevention. Equally important is a more universally accepted set of guidelines concerning prevention uses of medically important antibiotics, especially where alternative means of reducing the risk of disease are known to exist. McDonald's, in its Global Antibiotic Policy on stewardship, attempts to differentiate between &#;routine prevention&#; and &#;targeted prevention.&#;22 It would be appropriate that producers shift from using antimicrobials for routine prevention and instead identify critical life stages, or a set of risk factors, for when preventive use is justified. For instance, restricting antibiotic use to defined periods when animals are more vulnerable to infection because they are stressed or their immune systems are depressed, such as when chicks are moved into houses or when piglets are weaned. Alternatives to antibiotics, especially for prevention indications, are currently a topic of great interest to advocates, industry, and researchers.23 Notably, the WHO and many organizations do not currently distinguish between disease prevention, which is treating animals that do not have detectable pathogens but are at risk of being infected, and disease control, which involves treating groups of animals with varying numbers of detectable but often subclinical infections.3

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