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

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.