GoKawiilAn alarming increase in bacterial infections that don’t respond to many medicines has forced physicians to reach for outdated drugs at the back of the cupboard. In doing so, however, they might have stumbled on a wellspring of options for tackling the threat of antimicrobial resistance.
The unfashionable antibiotics in question are antimicrobial peptides (AMPs). Microorganisms, insects and mammals alike make thousands of these small proteins, typically no more than 60 amino acids in length. Many work by targeting parts of the bacterium’s protective layer that are crucial to its structural integrity, which makes it challenging for bacteria to evolve resistance to these drugs.
Nature Outlook: Antimicrobial resistance
Since the adoption of AMPs in the mid-twentieth century, they have fallen out of use because of their toxicity to humans. As resistance to other antibiotics increases, however, physicians are again having to use AMPs such as polymyxin as a last resort. But now, some scientists say that the peptides should be re-evaluated — not just as a final roll of the dice for a person in desperate need of treatment, but as a potentially rich source of fresh therapies.
Researchers think that tools such as molecular imaging and computer modelling that weren’t around when these drugs were discovered could help to overcome some of the problems that led to AMPs falling out of use. Some scientists are trying to tinker with the design of established peptides such as polymyxin; others are aiming to develop new ones using machine learning. And some researchers see in AMPs an opportunity to take a different approach to bringing antibiotics to market.
Poky peptides
In nature, AMPs help microbes to protect themselves against pathogens. Computational biologist Ewa Szczurek, who co-directs the Institute for AI for Health at Helmholtz Munich in Germany, estimates that about 30,000 have been documented. Of these, just a handful have been developed for use as antibiotics or in food preservation.
Compared with most small-molecule antibiotics, “AMPs represent a fundamentally different antimicrobial strategy”, says Niv Bachnoff, co-founder and chief scientific officer of the Jerusalem-based biopharmaceutical firm Omnix Medical.
Many conventional antibiotics target bacterial enzymes. AMPs, by contrast, usually target bacterial envelopes — the microbes’ protective coverings, which are made up of cell walls and lipid membranes. The peptides’ strong positive electrical charge draws them to the oppositely charged bacterial envelopes. Once there, “they make a hole in the membrane and stuff falls out”, says Szczurek.
This mode of destruction has distinct advantages. Because healthy human cells are typically neutral in charge overall, AMPs rarely go after them. And an assault on the bacterial envelope should be harder for microbes to defend against than the enzyme-focused attacks of many other antibiotics. “Even when resistance mechanisms do emerge, they often carry high fitness costs for the microbe,” says Bachnoff. The fast mechanism of action also reduces the time bacteria have to adapt, and makes resistance to AMPs less likely to develop.
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