Phosphoglucomutase A-mediated metabolic adaptation is essential for antibiotic and disease persistence in <i>Mycobacterium tuberculosis</i>

The long-term survival of <i>Mycobacterium tuberculosis</i> (Mtb) requires efficient use of host resources and uninterrupted access to host-derived nutrients. This is done by utilization of a highly flexible and integrated network of metabolic pathways. Phosphoglucomutase A (<i>pgmA</i>) is essential for glycogen biosynthesis, which acts as a nutrient reservoir and is known to modulate carbon flux in various pathogens. We, for the first time, investigated the role of <i>pgmA</i> in Mtb by creating a strain lacking this gene. The absence of <i>pgmA</i> hinders the survival of pathogens under nutrient-limiting and reactivation conditions. Our study shows that the lack of cell membrane-associated glycolipids in Δ<i>pgmA</i> compromises cell wall integrity and increases susceptibility to stress. Interestingly, Δ<i>pgmA</i> exhibits an enhanced growth phenotype on cholesterol compared to the wild type due to low cyclic adenosine monophosphate (cAMP) levels. Differential gene expression and ¹³C₃ carbon dilution analyses indicate that stored carbon as glycogen is crucial for Mtb survival under nutrient-limiting conditions. We demonstrate that <i>pgmA</i> is vital for Mtb growth within the host. This study highlights the critical role of <i>pgmA</i> in metabolic adaptation during nutrient starvation and reactivation and its implication on antibiotic and disease persistence. These insights are crucial for developing novel, shorter, and more effective anti-tuberculosis strategies.IMPORTANCEThis study for the first time investigated the role of metabolic enzyme phosphoglucomutase A (<i>pgmA</i>) in <i>Mycobacterium tuberculosis</i> (Mtb), revealing its crucial functions as a toggle switch between biosynthesis and growth. This work highlights the importance of <i>pgmA</i> in maintaining the metabolic flexibility of Mtb during the nutritional switch. The presence of <i>pgmA</i> is critical for the production of membrane-associated glycolipid, which helps maintain the cell wall integrity under various growth and stress conditions. This adaptability is pivotal for generating starvation-induced antibiotic tolerance in Mtb. In addition to the clinical context, these findings provide a mechanistic foundation for understanding adaptive strategies by Mtb to harsh environments and the development of drug-tolerant bacilli.