K. Barry Sharpless

Abstract The ability of compounds to permeate and accumulate in bacterial cells is a critical determinant of antibiotic efficacy. Better therapeutics are urgently needed for the human pathogen Mycobacterium tuberculosis, yet the cell envelope, including the mycobacterial outer membrane, represents a significant barrier for drug entry, and the chemical features governing permeation remain poorly understood.

Abstract Mycobacterium tuberculosis (Mtb) remains the world’s deadliest bacterial pathogen1. There is an urgent medical need to develop new drugs that shorten the treatment duration to combat widespread multi-drug-resistant and extensive-drug-resistant Mtb. Here, we present a preclinical covalent compound, CMX410, that contains an aryl fluorosulfate (SuFEx)2 warhead and uniquely targets the acyltransferase domain of Pks13, an essential enzyme in cell-wall biosynthesis.

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