The acetyltransferase CysE modulates virulence and drug resistance of Mycobacterium tuberculosis by interfering with oxidative stress responses

Acetyltransferases play a crucial role in biological processes by modifying a variety of substrates. However, their roles in the virulence of Mycobacterium tuberculosis (M. tb) are poorly understood. To systematically investigate the roles of acetyltransferases in M. tb, we constructed an acetyltransferase mutant library using CRISPR-assisted genome editing and screened for genes that are essential for mouse infection. Seven acetyltransferases were identified as essential for lung infection of M. tb. cysE, encoding a serine acetyltransferase, was confirmed to be required for virulence of M. tb in mice and its replication in macrophages. Further experiments revealed that mutation of cysE or inhibition of CysE by small molecular chemical increased sensitivity to clofazimine treatment. Finally, we demonstrated that cysE is involved in mitigating oxidative stress, which modulates the virulence and drug resistance of M. tb. Our study suggests that targeting cysE offers potential for the development of anti-tuberculosis drugs, particularly for enhancing treatment regimens for drug-resistant tuberculosis through the synergistic effect with clofazimine.