Growth arrest of Mycobacterium tuberculosis in acidic environments enhances their survival of antibiotic treatment

However, we have a poor understanding of how Mtb’s growth behaviors change at a single-cell level as the population responds to host environmental cues. Here we show that Mtb adapts to acidic conditions by increasing the proportion of bacteria in a growth-arrested state rather than uniformly slowing the growth rate of the entire population.

Bacteria in the growth-arrested subpopulation were more tolerant to treatment with ethambutol. Clinical strains in both neutral and acidic conditions have a higher proportion of bacteria in the growth-arrested state, suggesting that growth arrest is a bet-hedging mechanism that is important during infection. The PhoPR two-component system is thought to be a master regulator that enables Mtb to adapt to and survive acidic pH stressors, but we show that it is a partial regulator of the non-growing bacterial subpopulation and that other transcriptional regulators are involved.