Phosphoserine aminotransferase SerC is a central metabolic checkpoint and druggable vulnerability in Mycobacterium tuberculosis

Abstract

Serine metabolism is fundamental to the pathogenicity of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), yet its full metabolic scope and therapeutic potential remain unclear. Here we show that the phosphoserine aminotransferase serC is an essential metabolic node that coordinates central carbon and nitrogen flux and enables intracellular survival in the host. Deletion of serC caused severe growth defects across macrophage and murine infection models and rewired central carbon metabolism, reducing glycolytic, tricarboxylic-acid-cycle, and methylcitrate-cycle fluxes while altering one-carbon, branched-chain, and amino-acid biosynthetic pathways. Transposon sequencing identified sdaA-dependent serine deamination and the glycine cleavage system as key determinants of serine-based nitrogen assimilation, while revealing redundancy in serine transport. Our findings validate serine biosynthesis as a vulnerable, druggable metabolic target in Mtb and highlight it as a promising route for the development of urgently needed therapies against TB, which continues to kill millions of people each year.