Chaetocin: An In Vitro Bactericidal Compound That Disrupts Redox Homeostasis in Mycobacterium tuberculosis

The increasing prevalence of drug-resistant Mycobacterium tuberculosis underscores the urgent need for novel therapeutic strategies. We found that the natural product chaetocin exhibits in vitro bactericidal activity against drug-sensitive and drug-resistant M. tuberculosis strains. Biochemical and genetic analyses revealed that chaetocin exerts its antibacterial activity by disrupting bacterial thiol-redox homeostasis, with the thioredoxin reductase TrxB2 as a key mediator. Chaetocin treatment leads to a disruption of cellular thiol-redox homeostasis and accumulation of lethal reactive oxygen species. Notably, modulation of TrxB2 expression directly altered bacterial susceptibility to chaetocin, indicating that TrxB2 is involved in the response to chaetocin. These findings establish chaetocin as an in vitro active compound and a promising lead for further investigation targeting bacterial redox homeostasis and provide a promising foundation for the development of a new class of anti-tuberculosis agents.