1. The problem of AMR
There is no doubt that antimicrobial resistance (AMR) is one of the greatest health risks to emerge in the 21st century. The increase in multi-drug resistant strains of many bacterial pathogens raises the spectre of a post-antibiotic era in which previously treatable infections are fatal and routine surgery becomes a risky procedure. In response to the magnitude of the problem, the World Health Organization developed the priority list of AMR pathogens to aid in focusing resources and attention () [Citation1]. On this list multi-drug resistant Mycobacterium tuberculosis, which causes tuberculosis, is the highest priority since it has been the leading cause of death from an infectious disease for several years. Other priority pathogens on the critical list are carbapenem resistant Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacteriaceae.
Table 1. High priority pathogens.
A major issue in the development of new antimicrobials has been the withdrawal of the large pharma companies from this field. The lack of a return on investment for antibiotics, and the difficulties in obtaining regulatory approval, has been well-documented and explains this. While biotechnology companies are active in the field, there is a funding gap between the early discovery and development work and clinical trials which has not been filled. A second consequence of pharma withdrawal is the loss of a wealth of industry expertise in antibacterial drug development, which cannot be easily replaced.
A number of new incentives and initiatives have been launched in order to drive up interest; these include GARDP (Global Antibiotic Research & Development Partnership) and CARB-X (Combating Antibiotic Resistant Bacteria), which fund research and development, as well as incentives such as the Tropical Disease Priority Review Voucher Program, which can be applied to tuberculosis. The establishment of the Global Antimicrobial Resistance Research and Development Hub is a welcome addition, considering the large investment boost provided by the German government (500 million euros).However, the funding gap has not been closed and it remains to be seen whether these types of initiatives are sufficient to provide the economic and scientific stimulus required to generate the robust drug pipeline essential for attacking multiple pathogens.
2. Finding novel agents
One of the greatest challenges in modern drug development is the identification of new antimicrobial agents. As has been noted, many current drugs under development are derivatives of existing classes, and so may not be able to address resistance in all cases, although it is possible to develop derivatives which do not suffer from cross-resistance. Finding new classes which have new targets is a more difficult enterprise, but is critical [Citation1]. A range of approaches has been used historically to screen extensive libraries of either small molecules or natural products (extracts and/or purified products). The ‘rational’ approach has selected targets which are predicted to be both essential for viability and druggable, but this approach has failed in many cases [Citation2]. This has led to a recent upsurge in empirical approaches, using phenotypic screening, to find active agents with unknown targets. While the latter approach is showing some promise, the route to identifying targets and developing initial hits into drug candidates is lengthy and more complicated when structure-guided drug design is not available. In addition, the relevance of phenotypic models that can be used in the laboratory to the more complex environments and niches found during infection is variable. New screening approaches using more sophisticated methods that can mimic human infection more closely, such as ‘organ chips’ and multicellular models have not yet been applied to screening large libraries.
The low success of many phenotypic screening campaigns in discovering antibacterials is likely to be related to both the quality of the libraries, representing limited chemical space, and the inherent difficulty of finding compounds that selectively target bacteria. Large pharma libraries are biased toward compounds that target eukaryotic cells and are largely comprised of compounds made for a small number of therapeutic areas (which no longer includes antimicrobials). Thus, the types of molecules that have whole cell activity against prokaryotes are missing from these sets. The mining of natural products has been limited by the relatively small number of purified products available for screening; complex, diverse, extracts can be screened but deconvolution of activity coupled with repeated identification of the same compounds has limited its usefulness. However, more effort is being made to access previously untapped sources of natural products, for example, isolating organisms from inaccessible locations, e.g. deep sea vents, or from currently non-culturable sources, e.g. soil in order to find novel chemical entities that can form the starting points for drug development. In the latter case, technology used to identify the novel antibiotic teixobactin holds the promise of finding more active natural products from accessible sources [Citation3].
Pathogens present a range of challenges for compound penetration. The large differences in cell wall composition between Gram-negative and Gram-positive organisms imply a different set of characteristics for compounds to penetrate. In addition, for intracellular pathogens, an additional barrier is the requirement to enter the eukaryotic host cell to reach the biochemical target. The characteristics of compounds which can pass through cell wall and cell membranes are hard to predict. Recent work has developed computational models to predict the required physicochemical properties for compound penetration into Escherichia coli which can be used in structure-activity relationship studies to develop compound series into drug candidates [Citation4]. If predictive models were generated for other species, they would speed the development and decrease the investment required to generate novel analogs, by including rational design.
3. Tolerance and resistance
Treatment options for most bacterial pathogens have traditionally focused on selecting the shortest time and fewest doses for a single agent. In contrast, treatment of tuberculosis has traditionally used a combination drug regimen, currently comprising four drugs. Using drugs in combination can slowdown the emergence of resistance (since resistance to two agents is less frequent than to one). This approach is also used in treatment for HIV and cancer, where resistance is a problem. The concept of combining two or more antibiotics in order to prevent resistance, and in some case generate synergy between agents, is slowly gaining traction in targeting other pathogens. Debate still ranges over whether combinations are poor antibiotic stewardship, or an important mechanism for preventing the emergence of resistance [Citation5], but it is likely to become more frequent. However, the challenge of developing novel regimens is more complicated than for single agents. Current approaches have limited this to testing the best drug candidates in combination, but an approach which can identify synergistic or complementary combinations earlier in the pipeline to allow for concomitant development is preferable [Citation6–Citation8]
Antimicrobial resistance is an unavoidable consequence of the use of antimicrobials. Resistance to new agents has generally arisen within 10 years of their first clinical use. The selective pressure during treatment cannot be avoided, so that it seems inevitable that any one drug will ultimately fail. Antibiotic stewardship can help to slowdown the emergence of resistance and its spread. While antibiotic resistance is genetically determined and heritable, the phenomenon of antibiotic tolerance, in which susceptible organisms survive in the presence of an antibiotic, is common among bacterial species. Tolerance can often lead to the emergence of resistance, as it provides for cycles of growth during which genetic mutations occur. Eradicating tolerant or persistent populations during treatment would slowdown the emergence of resistance and shorten therapy. The challenge of targeting tolerant populations is that they often demonstrate tolerance to all antimicrobials. However, recent advances in understanding tolerance have identified new targets [Citation9]. Targeting organisms in different physiological states, e.g. in biofilms, and targeting virulence pathways such as quorum sensing are areas which have yet to be fully explored.
4. Alternative approaches to antibiotics
Due to the dearth of novel agents, there has been a renewed interest in alternatives to antibiotics; strategies such as phage therapy or host-directed therapy continue to generate interest, although they have not yet been clinically validated in modern trials. For example, boosting the host response to increase immune-meditated bacterial killing and, therefore, complete clearance has been proposed for tuberculosis. There are multiple pathways that could be targeted and while many of these have been demonstrated in model systems, no human trials have validated this approach, partly due to the challenge of demonstrating an effect in clinical trials [Citation10]. Adjunct therapy alongside existing antimicrobials can also be used. Therapy using naturally occurring bacteriophages to kill bacteria directly or to deliver a toxic payload has also been used in animal models and could provide an alternative approach. However, the delivery of phage particles, which are comprised of proteins and nucleic acids (and sometimes lipids) can provoke an antibody response which precludes repeated dosing [Citation11]. Alternative delivery strategies using the respiratory route could solve some of these issues [Citation12].
5. Antibiotic persistence in the environment
One of the overlooked aspects of AMR during drug development is the persistence of antibiotics in the environment. Aside from the presence of naturally occurring antibiotics in the soil, which can lead to selection for naturally resistant organisms, the accumulation of manufactured drugs is a problem. From a patient delivery perspective, the ideal drug should be stable at environmental temperatures over long periods of time. However, this can inadvertently lead to its persistence in the environment as a contaminant. While compounds that are rapidly degraded in the environment are desirable, this may be difficult to achieve without sacrificing drug stability in the clinic. However, minimizing the entry of antibiotics into the environment is a critical component of any AMR strategy [Citation13,Citation14].
6. Conclusion
While the prospect of increasing AMR infections is grim, there are a number of unexplored avenues which could be pursued to find new drugs and new drug targets. An increased impetus toward non-traditional screening and non-traditional approaches is required in order to strengthen the drug pipeline at all stages of discovery and development.
7. Expert opinion
Antimicrobial drug development is receiving more interest and attention with the recognition that resistance to current drugs has evolved at an alarming rate. However, current investment levels are insufficient to build and sustain the robust pipeline of new drug candidates needed to ensure new agents will be available for clinical use. New incentives and organizations are being established to address the issue, but a more diverse approach and a more coherent long term vision is required. Work on raising public awareness has borne fruit in establishing new incentives with government investments, but this needs to be continued and expanded. The danger of sinking once again into complacency is real.
The lack of chemical diversity in screening collections has not been addressed satisfactorily. Efforts to identify novel chemical scaffolds and learn from natural products need to be increased. The application of systems biology to mine genomes and synthetic biology to generate synthesis routes for novel antibiotics holds great promise. Current screening using simple laboratory conditions has largely exhausted the potential in chemical libraries available today. However, there may be value in mining these libraries again using different approaches. For example, the development of new screens to detect inhibitors of infection-relevant states and/or targeting virulence pathways deserves more attention. Antibiotic-tolerant bacterial populations can be targeted. Identifying synergistic or complementary combinations at an early discovery stage is attractive, although still somewhat challenging. Combinations can overcome tolerance and prevent the emergence of resistance. All of these approaches have promise, and the next decade should allow us to evaluate which have the most value.
Resistance to single new agents is likely to emerge and we need to build this assumption into our plans. Developing a robust pipeline with multiple new classes will mitigate this, but requires substantial investment. Approaches which minimize or overcome resistance, such as targeting antibiotic-tolerant organisms or developing combination regimens should be favored and intensified.
The challenge of developing alternatives to small molecules has not yet been met; natural product chemistry is under-resourced and the basic understanding required to develop adjunct therapies (immunotherapeutic or host-directed therapies) is not fully developed. Alternatives such as phage therapy have not been fully tested in the clinic.
The common theme among all of these approaches is the lack of resources. Although antimicrobial resistance is now more widely known and discussed, this has not translated into the funding needed to develop the drugs we will need for a healthy population in the 21st century.
Declaration of interest
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One referee declares having been a speaker for and/or has received research grants from Bayer and Merck (tedizolid), Melinta and Menarini (delafloxacin), Ferrer (ozenoxacin), AstraZeneca (avibactam), GlaxoSmithKline (gepoditacin) and Debiopharm (afabicin). He also has been member of the Governance Body of DRIVE-AB, a EU-sponsored program examining the economic aspects the discovery, development, and commercialization of novel antibiotics
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References
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