The bacterium Acinetobacter baumannii is a portrait of resilience. The microorganism causes a variety of infections, and its desiccating ability means it can persist for weeks in hospital vents, computer keyboards, and human skin. Its metabolic and genetic flexibility has allowed it to become resistant to the few antibiotics that can pass through its two protective mobile membranes. Antibiotic-resistant microbes kill more than a million people each year. The global risk posed by A. baumannii has placed this microbe among the most sensitive on the World Health Organization’s (WHO) Priority Pathogen List.
Two studies published Jan. 3 in Nature report a newfound elegance of drug seekers to fight A infections. coli. baumannii (C. Zampaloni et al. Nature https://doi. org/10. 1038/s41586-023-06873-0 (2023); K. P. Pahil et al. Nature https://doi. org/10. 1038/s41586-023-06799-7; 2023). One of those compounds has already been in clinical trials and has yet to be approved for clinical use. .
The obstacles to the progression of such compounds are not just scientific: the economic incentives are inadequate for many corporations to take the risk. As the risk of resistance increases, the foreign network will have to do more to advise promising drugs from the lab to the bedside.
The new compounds block the bacteria’s ability to send key building blocks to where they are needed by binding to a new site on the bacteria. There are other compounds that target this pathway, but A. Baumanni is resistant to it. One of the molecules, called zosurabalpin, killed several resistant strains of A. coli. Baumanni in culture and, in mice, a strain resistant to all available antimicrobials. Top-line effects are expected from clinical trials of this compound this year.
It is rare to get antibiotics with a new mode of action into the clinic — only one in 30 candidates makes it as far as testing in people. Even when a new drug does get through clinical trials and is approved for use, it is often held in reserve for worst-case scenarios, for fear that widespread use would hasten the day when microbes develop resistance to it.
The end of the initial phase of clinical trials will be just the beginning. Further studies will then be needed to assess the threat of zosurabalpine resistance progression in clinical settings. Then, if the drug is approved, someone will have to pay for it. The advertising market is depressing because of its design. A breakthrough of a new antibiotic costs more than $1 billion, but the reluctance to use it on a giant scale means it will most likely generate less than $100 million a year once it hits the market. The WHO and others have warned governments about the scale of the finish, along with the growing threat of antimicrobial resistance. Some governments have responded by offering incentives to inspire the industry to rise to the challenge. But there have been many more words than deeds.
The solution, fitness economists say, lies in a combination of incentives to expand new antimicrobial drugs. “Nudge” methods are designed to reduce costs and would possibly involve greater government investment for early-stage research. “Pull” approaches praise corporations that scale up effective antibiotics: for example, governments may also simply guarantee a minimum point of purchase, similar to complex vaccine purchases during the COVID-19 pandemic. Governments tend to lean more towards pressure methods. Economists say they want to step up their efforts. But they will also have to take the lessons learned from the COVID-19 vaccines, and also ensure that costs and contracts are transparent, which has not been the case during the pandemic.
The UK has been a leader in this regard. In 2019, it announced a “subscription” program whereby companies get a consistent annual payout based on the price of a fitness drug, rather than the number of doses sold. Other countries are contemplating similar projects. In the United States, a bipartisan team of lawmakers supports the Pioneering Antimicrobial Subscriptions to End Rising Resistance (PASTEUR) Act, which would create a similar program. But the law has struggled in the U. S. Congress since it was introduced in 2020. Nor has the Union been able to adopt the applicable legislation. It is time for governments to move from mirror image to action.
Understandably, there are some doubts: The underwriting style would put further pressure on fitness budgets already under pressure from drug costs driven by high levels of inflation. But there’s a way to look at those payments: as insurance against long-term fitness formula crises. If governments succeed in making the market for those drugs viable, it will also inspire corporations to invest.
In September, the United Nations General Assembly will host a high-level meeting to discuss antimicrobial resistance — the first such meeting since 2016. This will highlight the problem and offer an opportunity to extract real commitments from member states. The last meeting was transformational in one respect: more than 150 countries agreed to draw up action plans to address antimicrobial resistance.
But an action plan is not the same as an action: many plans are not fully implemented or funded. This wants to change. The discovery of compounds with promising preclinical activity is exactly what the doctor ordered. But without a strategic funding plan, this solution can sit on the shelf for years. In the meantime, A. baumannii and its ilk will continue to pose a pressing health risk with limited remedy options.
Nature 625, 7 (2024)
It’s me: https://doi. org/10. 1038/d41586-023-04086-z
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