Abstract
Hostile environmental cues cause Mycobacterium tuberculosis to enter a state of slow growth for survival. However, the underlying regulatory mechanism remains unclear. DnaA is essential for DNA replication initiation and represents an efficient target for growth regulation in bacteria. Here, we show that the nucleoid-associated protein NapM is a DnaA antagonist, protecting M. tuberculosis from stress-mediated killing. NapM can be induced by diverse stressful signals. It binds to DnaA to inhibit both its DNA replication origin-binding and ATP hydrolysis activity. As a DnaA antagonist, NapM inhibits the mycobacterial DNA synthesis in vitro and in vivo in M. tuberculosis. Furthermore, we show that NapM contributes to the survival of M. tuberculosis under stress and within macrophages during infection. Our findings provide a previously unidentified mechanism of mycobacterial survival under stress and also suggest NapM as a potential drug target for tuberculosis control.