Youcai Hu's group in the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, has revealed a completely new type of self-resistance mechanism in the biosynthesis of a fungal macrolide antibiotic involving a cycle of extracellular oxidative activation and intracellular reductive inactivation. This work entitled “Self-Resistance in the Biosynthesis of Fungal Macrolides Involving Cycles of Extracellular Oxidative Activation and Intracellular Reductive Inactivation” has been published online in Angewandte Chemie International Edition on December 15, 2020.
Many microbes produce antibiotics to inhibit or kill the competitors for resources.To avoid self-harm, antibiotic-producing microbes have developed a variety of resistance strategies using antibiotic resistance genes (ARGs). Because many clinically relevant ARGs found in human pathogens have been traced to antibiotic-producing microbes, they are thought to be reservoirs of resistance genes. Therefore, revealing the resistance mechanisms in antibiotic-producing microbes are meaningful to the discovery and development of new antibiotics. By a combination of heterologous expression, biochemical assays, and protein subcellular localization using fluorescence microscopy, Hu’s group revealed the self-resistance mechanism through elucidating the biosynthesis of a 16-membered macrolide antibiotic, A26771B (1). In the biosynthesis of 1, monosuccinylation by BerkF not only generates prodrug 2 but also facilitates its efflux out of the cell. The secretory protein BerkD then catalyzes the oxidation of 2 extracellularly to form the antibiotic 1. Remarkably, 1 can be reduced back to 2 by the intracellular protein BerkC to avoid self-harm once 1 enters cell. Thus, a unique cyclic self-resistance mechanism involving reversible conversion between a ketone and alcohol was uncovered in the biosynthesis of antibiotic 1. Interestingly, the prodrug 2 was recycled without consumption during the self-protection process. Since many bioactive natural products, especially fungal macrolide antibiotics, contain the γ-keto-α,β-unsaturated carbonyl group found in 1, reversible ketone-alcohol modification might be a generic self-resistance mechanism in natural product biosynthesis. This finding not only expands the understanding of resistance toward macrolide antibiotics, but also guides efforts to develop new antibiotics.
Link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202015442
