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During a tenure as director general of the WHO, a past official famously remarked that all of the “easy” antibiotics had long since been discovered. The argument was that in tackling the urgent danger of drug-resistant bacterial infections, we would struggle to discover new medicines – or conserve the current arsenal – without developing new ways of operating. This view proved accurate.

A Sluggish and Challenging Development Path

Since the late 2010s, only 16 antibiotics have received broad official clearance – mostly close relatives of drugs already in use and thus unlikely to overcome bacterial resistance for an extended period. The development of novel compounds is a lengthy and financially unattractive endeavor, given that curative medicines are not as profitable as those treating longer-term conditions. The scientific outlook remains grim.

A Glimmer of Optimism and a New Model

Nevertheless, the recent announcement of a pair of novel FDA-approved drugs for gonorrhea is good news and, importantly, validates a new way of incentivising development. One of the new drugs, a compound called Zoliflodacin, is the result of a novel kind of partnership between a Swiss non‑profit and a drug firm. The public health partnership provided funding and organised testing phases to offset expenses and clear approval processes. This sort of assistance in advance helps steer the industry towards areas of most pressing public health necessity.

This model and a separate lauded revenue guarantee scheme – initiated to guarantee revenue to companies that invest in certain antimicrobials – represent the best hope of maintaining a trickle of new drugs from the current system.

The Unavoidable Problem of Drug Resistance

But even hurrying the production of compounds in the pipeline isn't sufficient. Zoliflodacin is sometimes described as a novel type of antimicrobial, indicating it attacks a part of the infectious bacteria that no other drug does, in principle forcing the pathogen to start from zero in evolving a countermeasure to it. Scientists and physicians are relieved to have a new drug for gonorrhea – which has strains resistant to all existing treatments – but warn that future resistance to this compound is certain.

As has grown customary with recent antimicrobials, there is consequently an debate about whether it should be held in reserve, rationed to extremely drug-resistant cases only – limiting its use to settings where sophisticated diagnostics is available. This kind of rational strategy should be the global standard, but often can't be implemented readily in many parts of the world.

A Dwindling Stream of Innovation

More broadly, it is difficult to see where the flow of additional new antibiotics we need could realistically come from. The aforementioned comment acknowledged the fact that searching the living world for natural sources – as with penicillin – has had diminishing returns. The application of AI has been proposed to accelerate the discovery process, although a highly-touted early candidate identified in 2020 has not yet progressed past preclinical studies. Fully lab-created compounds, that are mainly or fully synthesized, are constantly in research, but often confront the fundamental rules of molecular science – the fact that we envision a molecule doesn't mean we can synthesise it without great difficulty.

Moving Quickly to Stand Still

The prevailing scientific evaluation is that when it comes to antibiotics, we must run very fast truly just to stay in the same place. Careful, globally managed use is the only way to maintain our advantage. Sadly, the scale of forthcoming breakthroughs is going to seem meager in contrast to the curative bonanza of the previous century.