Aldehyde inactivation of the RicR regulon sensitizes <i>Mycobacterium tuberculosis</i> to copper

ABSTRACT Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. While M. tuberculosis can persist in the presence of host-derived antimicrobials like nitric oxide and copper, bacteria defective for proteasome activity are highly sensitive to these molecules, making the proteasome an attractive target for drug development. Previous work linked nitric oxide susceptibility with the accumulation of at least one aldehyde in an M. tuberculosis mutant lacking proteasomal degradation. In this study, we show that this aldehyde accumulation is also responsible for copper sensitivity in this strain. Furthermore, we show the exogenous addition of aldehydes to wild-type M. tuberculosis cultures sensitizes bacteria to copper. We determined that aldehydes directly affect the activity of two members of the RicR ( r egulated i n c opper r epressor) regulon, resulting in the reduced production and function of critical copper-responsive proteins. This study is the first to mechanistically describe how aldehydes can render M. tuberculosis susceptible to an existing host defense, and could support a broader role for aldehydes in controlling M. tuberculosis infections. IMPORTANCE M. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes target critical bacterial survival pathways, making aldehydes a previously unappreciated antimicrobial defense.