Targeting antimicrobial resistance

For many years, antimicrobial resistance (AMR) has been recognized as a serious threat to public health, and the problem is getting worse. Bacteria have developed resistance to once-innovative antibiotics—and now, owing partly to their overuse—there are increasingly limited options for combating a growing number of bacterial pathogens that cause serious infections.

Despite this impending crisis, the development of new antibiotics has long been stuck in a rut, largely owing to the lack of a sufficient market for new antibiotics. Consequently, larger pharma companies have exited the field or downsized their involvement in it to focus on other therapeutic areas, and smaller companies working in the field have struggled to make a return on their investments, even when they have managed to overcome the substantial challenges to bring a novel antibiotic to market. The fragile antibiotic innovation ecosystem and the failed market for new drugs have created the perfect storm, and an urgent need for action. Here, we highlight the role of dealmaking (Table 1), partnerships and global initiatives (Fig. 1) in tackling the AMR crisis.

Sparse development pipeline

AMR remains a looming threat because the continual emergence of antibiotic resistance is outpacing the emergence of new antibiotics from the weak development pipeline. The problem is particularly acute for Gram-negative pathogens, such as Acinetobacter baumannii, for which it is inherently harder to develop new antibiotics because of the structure of their cell wall. Agents with new mechanisms of action could be especially useful in combating AMR, but the last entirely new class of antibiotics was discovered in the 1980s (Nature 586, S50–S52; 2020).

Indeed, many of the new therapies in development lack novel mechanisms of action. According to the Pew Charitable Trust, 43 antibiotics were in clinical development in March 2021, with around half having the potential to treat infections caused by high-priority Gram-negative bacteria. However, only ~25% of the 43 agents represent a novel drug class or mechanism of action, and none of this subset targeted the high-priority Gram-negative pathogens.

Pipeline partnerships to the fore

With the aim of helping to address the withdrawal of large pharma companies in the field, several initiatives have been established in the past decade to catalyze early-stage research and development (R&D) for novel antibacterial agents (Fig. 1). For example, CARB-X—a global public–private partnership with funders including the US government, the Wellcome Trust and the AMR Centre in the UK—launched in 2016 to support the progression of innovative antibacterial agents into clinical trials. So far, it has invested US$361 million in 92 projects, including conventional antibiotics as well as other antibacterial approaches such as phage-based therapies.

However, even with such support for early-stage pipelines, it has become apparent that unless the factors underlying the market failure for antibiotics are addressed, there will be a continued lack of companies prepared to make the substantial and high-risk investments in later-stage clinical trials to bring products to market. Recognizing this problem, 24 pharmaceutical companies came together in 2020 to launch the AMR Action Fund, with the aim of investing $1 billion in small biotech companies over the next 8–12 years to support 15–20 phase 2 and 3 trials of novel antibiotic candidates (Nat. Rev. Drug Disc. 19, 575–576; 2021).

Encouragingly, there are early hints in dealmaking activity that efforts to support antibiotic R&D could be having an impact. For example, in July this year, Pfizer made a $40 million equity investment in Spero Therapeutics—a company that has received support from CARB-X—and entered into a licensing agreement for SPR206, a next-generation polymyxin candidate in development to treat serious multi-drug-resistant Gram-negative infections.