New antibiotics to combat One Health AMR

Introduction

The discovery of antibiotics marked the beginning of a new era in modern medicine, but now, 1 century later, we are witnessing their demise. Antimicrobial use is the single biggest driver of resistance development. Antimicrobial consumption is increasing across the One Health space including the use of antibiotics as growth promotors in food producing animals and for prophylaxis in intensive farming in some countries.¹ Unfortunately, the extensive use of antibiotics is combined with a decline in antibiotic research, contributing to a rapid rise in untreatable infections by antimicrobial-resistant bacteria. Infections caused by these resistant bacteria cost the medical and veterinary industries billions of dollars per year and are increasingly affecting global human and animal health, as well as food stability and production. In support, the World Health Organization (WHO) has declared that antimicrobial resistance (AMR) is one of the top ten global public health threats facing humanity.²

Several organisms on the WHO list of pathogens that are deemed to be the most critical priority in need of new drug development are opportunistic pathogens of relevance to both human- and veterinary health (e.g. carbapenem-resistant Acinetobacter baumannii, CRAB; carbapenem-resistant Pseudomonas aeruginosa; and carbapenem-resistant or third generation cephalosporin-resistant Enterobacterales), as well as agriculture and the environment, highlighting the One Health dimensions of this problem (Fig. 1).³ Drug discovery efforts are not able to keep pace with the increase in resistance, hence antibacterials with novel mechanisms of action, not subject to existing resistance mechanisms, are needed.

Fig. 1.

Antimicrobial resistance (AMR) is a One Health problem. Diagram indicating the dissemination of antimicrobials as well as AMR organisms and their genes throughout the One Health spectrum.

Human antibiotics

The number of antibiotics in the clinical pipeline has been regularly reviewed in a consistent format since 2011,^4–8 providing an opportunity to assess changes in the pipeline over the past decade. The most recent review, along with others of both clinical⁹ and preclinical¹⁰ candidates, highlight that there are only ~60 in clinical development, substantially less than other therapeutic areas such as oncology, or even the specific disease of COVID-19. Critical analyses^11,12 of these clinical candidates highlights the lack of novelty: most are derivatives of established antibiotic classes, albeit generally designed to overcome at least some of the known resistance mechanisms present at the time of their initial development. However, given that initial development is generally more than a decade before approval, resistance often continues to evolve beyond what the new drugs can cope with. New β-lactamase and β-lactamase inhibitor combinations dominate the most advanced candidates, reflected by the recent (European Medicines Agency in January 2024¹³ and US Food and Drug Administration in February 2024¹⁴) approval of Exblifep (cefepime and enmetazobactam). However, there is hope, both in an increase in the number of candidates entering clinical trials, and in innovation of new chemical scaffolds acting on novel targets. The former is highlighted by the number of candidates in the first stage of human testing (Phase 1), which has doubled from 12 in 2011 to 25 in 2022 (see Fig. 2).⁷ This positive trend potentially reflects the effect of initiatives designed to prime the pipeline, such as the antibiotic funding agency CARB-X.¹⁵ One example of the latter is the advanced preclinical development of a new macrocyclic peptide, zosurabalpin, that inhibits a lipopolysaccharide transporter essential for moving lipopolysaccharide to the bacterial surface, disrupting formation of the outer-membrane of Gram-negative bacteria.^16–18 It is specific to A. baumannii, and retains activity against one of the most dangerous strains, CRAB. In the past, a species-selective antibiotic would not have been progressed due to the difficulty in rapidly diagnosing an infecting strain and the reduction in market size, but advances in diagnostics and antibiotic market incentives mean that a viable pathway may now be possible.

Fig. 2.

Increase in clinical candidates from 2011 to 2022 (adapted from Butler et al.⁷).

Another example of pathogen-specific antibiotic candidates with novel mechanisms of action, is inhibitors of FtsZ, a critical protein in the bacterial cell-division machinery. The 3-methoxybenzamides (‘benzamides’), exemplified by the early progenitor PC190723, are well-characterised FtsZ inhibitors that bind into the interdomain cleft of FtsZ to disrupt GTPase activity.¹⁹ An important trait of the benzamide class of FtsZ inhibitors is their ability to synergise with beta-lactam antibiotics, thereby reversing beta-lactam resistance at concentrations much below their own inhibitory concentrations. Significant efforts by Taxis Pharmaceuticals identified TXA709, a prodrug form of the benzamide PC190723. This orally active anti-MRSA agent, designed to be used as an adjunctive therapy in combination with ‘obsolete antibiotics’, successfully completed Phase I clinical trials, representing a major advancement in anti-FtsZ drug discovery. In 2021, the WHO named TXA709 as one of only two (out of twenty-six) antibacterials targeting WHO priority pathogens that meet all the WHO innovation criteria.²⁰ New analogues of TXA709 in early development have been designed to target an extended spectrum of Gram-positive pathogens, including vancomycin resistant E. faecium.²¹

Animal antibiotics

The global magnitude and pace of resistance development to existing drug classes in veterinary medicine²² is exacerbated by the bond between humans and animals – particularly with companion animals,²³ the limited range of registered drug classes, the risk of transfer of resistance genes through the food chain²⁴ and the rapid development of pan-resistance in one of the most important animal pathogens, enterotoxigenic E. coli (ETEC).²⁵ However, in Australia, antimicrobial stewardship measures are in place to prevent and manage AMR in food producing animals. The Expert Advisory Group on Antimicrobial Resistance (AGAR) tests and collects data on the level of AMR, whereas The Australian Pesticides and Veterinary Medicines for Agricultural and Veterinary Chemicals (APVMA) assesses the risks and registers the supply, distribution and sale of veterinary antibiotic products. Such coordinated information gathering and strict regulation of antimicrobial use together with ongoing surveillance by the Department of Agriculture, Fisheries and Forestry (DAFF) accounts for the low level of AMR in food animals in Australia.

Although there are effective steps to monitor, prevent and manage AMR in veterinary medicine in Australia, the available literature indicates that combination therapy, development of new drug classes, phage therapy and novel efflux pump inhibitors are critically important new approaches for treating multidrug-resistant Gram-negative veterinary pathogens in the global context.²⁶ Given that the discovery and development of new antibiotics is very slow, drug combination can be a promising approach to extend the life of existing antibiotics in veterinary practice. Indeed, combination antibiotic therapy is now frequently used to treat severe Gram-negative (especially carbapenem-resistant Enterobacterales, CRE) infections, particularly in the absence of evidence-based treatment options.²⁷ Nonetheless, the justification for the best approach would necessarily require consideration of several factors including time to drug discovery, cost and propensity to overcome rapid resistance development. Additionally, new veterinary antibiotics against intracellular veterinary pathogens are urgently needed. For example, brucellosis is a worldwide zoonotic disease caused by Brucella spp.^28,29 and failure of regular treatment with the usual antimicrobials (quinolones, doxycycline, rifampicin, streptomycin and aminoglycoside alone or in combination) have been reported recently with emergence of AMR.³⁰

Although the risk of AMR transmission of anthropogenic or zoonotic origin is low,^31–35 the overarching guiding principles on antimicrobial use in veterinary practice will necessarily involve reduction in antimicrobial use, preserving the lifespan of currently registered animal antibiotics and finding new ways of managing microbial infections or by developing animal species-only drugs. Such activities will include regular AMR surveillance, avoiding the use of critically important antimicrobials (e.g. third generation cephalosporins), using safe alternatives to antibiotics (e.g. probiotics, vaccines, electrolysed oxidising water), development of new, rapid diagnostics to reduce unnecessary and inappropriate use of antimicrobials as well as registration of animal and pathogen-specific only drugs.

The recently established (2023) Australian Research Council (ARC) Industrial Transformation Training Centre, CEAStAR (the Centre for Environmental and Agricultural Solutions to Antimicrobial Resistance, see www.ceastar.org.au), was assembled to build Australia’s capability in addressing AMR by training the next generation of antimicrobial researchers. Led by two universities (The University of Queensland and The University of Adelaide), it focuses on industry-driven research projects that advance the development of potential commercial products provided by seven industry partners. These include new antimicrobials, antibiotic potentiators, non-antibiotic alternatives, and methods for environmental and microbiome monitoring. Notably, the awareness of the dangers of using antibiotics in agriculture is reflected by the types of projects: only one of the partners is developing what could be considered a traditional small-molecule direct acting antimicrobial, and this is a novel class, not used for humans.

Looking forward

For both human and veterinary antibiotics, a promising avenue for antimicrobial drug discovery is development of adjuvants that do not necessarily have antimicrobial action by themselves, but can, for example, act as resistance breakers to overcome resistance mechanisms and restore the activity of existing antibiotics.³⁶ This strategy can increase the lifetime of currently used antibiotics as well as restore activity of obsolete antibiotics. Notably, nearly half of the 28 small molecules active against Gram-negative bacilli that are currently in clinical trials are new beta-lactamase inhibitors (the progenitor adjuvant class) combined with existing beta-lactam antibiotics.³⁷ Other types of resistance breakers include efflux pump inhibitors. Drug efflux pumps are proteins that expel many different classes of antibiotics from bacterial cells thereby conferring multidrug resistance to these bacteria hence efflux pump inhibitors have the potential to restore the activity of multiple classes of antibiotics.³⁸ Despite the obvious advantages of efflux pump inhibitors and efforts by many research groups including ours,³⁹ efflux pump inhibitors are yet to progress to clinical trials.

Conclusion

The rapid rise in antimicrobial resistance development has coincided with a sharp decline in new antibiotic development due to the departure of most pharmaceutical companies from the field, a logical response to the poor return on investments. Concerns that the antimicrobial pipeline will run dry portend a future where there will be few or no treatment options for infections caused by resistant pathogens. Concerted international efforts funded by public and private investment, such as the AMR Action Fund, CARB-X and GARDP, have started to pay off and the number of antimicrobials in the clinical pipeline has slowly increased over the last few years. Encouragingly, the pipeline also now contains an increasing number of antimicrobials against new targets or with novel mechanisms of action.