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Drug discovery: Building better antibiotics

Nature

September 24, 2020

A synthetic approach to creating new antibiotics that could overcome antibiotic resistance is described in Nature this week. One of the compounds created using the technique is shown to be effective against resistant bacterial strains in a mouse model of bacterial infection.

Most antibiotics in clinical use are derived from natural products, which are subject to resistance mechanisms that have arisen through coevolution. For example, a family of antibiotics called group A streptogramins are rendered ineffective against bacterial strains that express virginiamycin acetyltransferase (Vat) enzymes, which can deactivate the antibiotic. Ian Seiple and colleagues report a method for making synthetic group A streptogramins that can overcome the resistance conferred by Vat enzymes.

Creating antibiotics from scratch in the laboratory can be a slow process, as these complex molecules require multiple highly customized chains of reactions. Seiple and colleagues speed things up by taking a modular approach. They use a basic scaffold, based on a naturally occurring group A streptogramin, and add interchangeable molecular building blocks (that can bind to cellular components of bacteria, but are less susceptible to Vat binding) to produce 62 analogues of group A streptogramins. One of these compounds shows activity against streptogramin-resistant strains of Staphylococcus aureus and is effective in a mouse model of bacterial infection. The authors propose that their method could extend the clinical longevity of the streptogramin class of antibiotics. In an accompanying News and Views, Daniel Blair and Martin Burke suggest that this work could aid the development of group A streptogramins that mitigate Vat-mediated resistance while retaining potent antibiotic activity.

doi: 10.1038/s41586-020-2761-3

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