Bacteria have developed resistance to so many antibiotics that a familiar adage about these lifesaving drugs is “use ’em and lose ’em.”
Ideas to break this cycle and create a market for new antibiotics include the proposed PASTEUR (Pioneering Antimicrobial Subscriptions To End Upsurging Resistance) Act of 2023, which has been reintroduced in Congress.1 Essentially, the bill introduced into the Senate would establish a committee of experts to create a list of the multidrug-resistant pathogens that pose the greatest risk to human health. A fund then would be created to pay pharmaceutical companies that develop drugs for the listed threats.
Currently, the market for antibiotics is “broken,” and companies do not see much incentive for developing these drugs, said Henry Skinner, PhD, MJur, CEO of the Antimicrobial Resistance (AMR) Action Fund. AMR is a public-private partnership investing in the development of new antibiotics, Skinner explained at a webinar held by the Harvard T.H. Chan School of Public Health.
“Antibiotics are unique in that the latest antibiotic we develop might work for all types of infections,” he said. “But we don’t want to use it where the old antibiotics [still] work because we don’t want resistance to the new antibiotic. So that means we hold it in reserve. We put it behind glass, and only in an emergency do we break the glass.”
The typical way of rewarding the value of a drugs — volume of use — does not work for antibiotics. In fact, the greater the volume of distribution and use, the more likely that the first signs of resistance will appear in bacteria, ultimately making them ineffective.
“We’re [making antibiotics] ineffective for the next generation,” Skinner said. “The market doesn’t work because there is no return on investment. How do we incentivize people to invest in this risky science? To take artificial intelligence [AI], and to convince our brilliant scientists — who deliver such great public health benefits in other areas of healthcare — to work in this space where we need them?”
A ‘Pull Incentive’
One solution is the PASTEUR act, which the United Kingdom is rolling out in similar form. These initiatives recognize the value to the healthcare system of a new antibiotic.
“It’s a ‘pull incentive,’” Skinner said. “If you make a good new antibiotic, we guarantee there will be some money to return on that investment to make sure that we have [drugs] available as a public good for patients. And, so, this is insurance, if you will, that incentivizes investors to take the risk, for scientists to commit their life and resources to make these new antibiotics.”
We have been warned time and again that the dwindling efficacy of antibiotics and the lack of new drugs in the pipeline could open a hellish gate to a post-antibiotic era where once-routine infections become serious and even deadly.
How does this happen? The simplest explanation is that antibiotics kill off drug-susceptible bacteria, opening a niche or “selecting out” those with innate drug resistance to proliferate. Bacteria also can transfer drug resistance mechanisms on mobile plasmids to other bacteria.
Bacteria evolved resistance to killing chemicals thousands of years before antibiotics existed. Researcher Brad Spellberg, MD, an infectious disease physician, says microbes found in ancient underground caves were naturally resistant to antibiotics they could not possibly have been exposed to — synthetic drugs developed in the 20th century. “These results underscore a critical reality: Antibiotic resistance already exists, widely disseminated in nature, to drugs we have not yet invented,” he noted.2
Globally, antimicrobial-resistant bacteria kills nearly 1.3 million people per year, more than human immunodeficiency virus/acquired immunodeficiency syndrome or malaria, Skinner said. In the United States, somewhere between 35,000 and 50,000 people die every year from AMR, and probably another 50,000 from Clostridioides difficile a secondary consequence of the use of antibiotics, Skinner said.
“The projections are, by 2050, if we don’t address this problem and stay ahead of it, 10 million people will die around the globe annually and cost the economies of the world trillions of dollars,” he said.
Seeking New AI Platforms
Akhila Kosaraju, CEO and president at Phare Bio in New York City, is involved in several projects using AI to find ways to develop new antibiotics.
“You can see how this problem hits every aspect of the health system,” she said at the webinar. “What we’re trying to do at Phare is really take it on at the earliest stages. Using AI for antibiotics, we feel that it addresses a very particular part of the problem that is amenable to solutions.”
In the golden age of antibiotics in the 1940s and 1950s, 26 new antibiotics were developed in 20 years, she noted.
“Now we are at an inflection point where we could get ahead of this and not get to this 10 million deaths by 2050,” Kosaraju said. “What we absolutely need now is new mechanisms — true, novel chemical spaces to work with. And that’s why we’re trying to use computational tools to address this.”
Using AI to develop antibiotic development could be similar to the decade of research that went into developing messenger ribonucleic acid “plug and play” vaccines that were critical when SARS-CoV-2 came out of China in 2020, she said.
REFERENCES
- Pioneering Antimicrobial Subscriptions to End Upsurging Resistance Act, S. 1355, 118th Cong., 1st Sess. (2023).
- Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med 2013;368:299-302.
Bacteria have developed resistance to so many antibiotics that a familiar adage about these lifesaving drugs is “use ’em and lose ’em.” Ideas to break this cycle and create a market for new antibiotics include the proposed PASTEUR (Pioneering Antimicrobial Subscriptions To End Upsurging Resistance) Act of 2023, which has been reintroduced in Congress.
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