Weakening TB by targeting serine metabolism

Tuberculosis remains a leading infectious killer worldwide, driven by the bacterium Mycobacterium tuberculosis (Mtb). Scientists are searching for new vulnerabilities in the microbe’s metabolism that could point to novel treatments. Serine, one of the amino acids cells use to build proteins and to shuttle carbon and nitrogen around, is already known to be important for Mtb’s ability to cause disease, but how central it is and whether it can be exploited therapeutically was not fully clear. In work led by Khushboo Borah Slater, researchers focused on phosphoserine aminotransferase serC, an enzyme that sits at the heart of serine biosynthesis. By studying Mtb strains lacking serC and following their behavior in host cells and animal models, the team set out to map how disrupting serine production affects the bacterium’s core metabolism and ability to grow inside hosts. The goal was to test whether blocking serine biosynthesis could be a viable route to weakening Mtb and improving TB treatment options.

The investigators deleted serC and tested the mutant bacteria in macrophage and murine infection models. Loss of serC caused severe growth defects in these infection settings, showing that the enzyme is required for survival in host environments. Metabolic analysis revealed that removing serC rewired central carbon metabolism: glycolytic flux, tricarboxylic-acid-cycle flux, and methylcitrate-cycle flux were all reduced, and pathways involved in one-carbon metabolism, branched-chain biosynthesis, and amino-acid production were altered. To probe how Mtb handles nitrogen when serine pathways are disrupted, the team used transposon sequencing, which pinpointed sdaA-dependent serine deamination and the glycine cleavage system as key determinants of serine-based nitrogen assimilation. Transposon sequencing also revealed redundancy in serine transport, indicating the bacterium has more than one way to import serine from its environment. Together, these results show that serC occupies a central metabolic node and that blocking it cascades through multiple pathways important for Mtb growth.

The study validates serine biosynthesis, and specifically phosphoserine aminotransferase serC, as a vulnerable and druggable metabolic target in Mtb. Because deletion of serC cripples the bacterium’s core carbon and nitrogen fluxes and prevents robust growth in host cells and animals, drugs that inhibit serC or key supporting pathways could have strong anti-tuberculosis effects. The identification of sdaA-dependent serine deamination and the glycine cleavage system as important nitrogen-handling routes highlights additional targets and points to potential combination strategies that would limit the bacterium’s ability to compensate. The finding of redundancy in serine transport suggests that inhibitors may need to be combined with other metabolic blockers to be fully effective. Overall, focusing on serine metabolism offers a promising route for developing new therapies against TB, an urgent need given that the disease continues to kill millions of people each year.