Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in <i>Mycobacterium tuberculosis</i>

Abstract

Significance A better understanding of essential processes in Mycobacterium tuberculosis ( Mtb ) is required for the development of new chemotherapeutics. Isocitrate lyase (ICL) and malate synthase (MS) function in the glyoxylate shunt, a pathway required by Mtb to metabolize fatty acids (FAs). Here, we demonstrate that Mtb MS enables growth and survival on fatty acids through its ability to simultaneously detoxify a metabolic byproduct arising from the initial assimilation of acetyl coenzyme A (acetyl-CoA), glyoxylate, while assimilating a second molecule of acetyl-CoA. We further show that MS depletion during acute and chronic mouse infections kills Mtb . These studies expand our fundamental understanding of the glyoxylate shunt and biologically validate MS as an attractive drug target in Mtb .