Aldehyde accumulation in with defective proteasomal degradation results in copper sensitivity.

is a major human pathogen and the causative agent of tuberculosis disease. is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and copper (Cu). However, with defective proteasome activity is highly sensitive to NO and Cu, making the proteasome an attractive target for drug development. Previous work linked NO susceptibility with the accumulation of -hydroxybenzaldehyde (HBA) in mutants with defective proteasomal degradation. In this study, we found that HBA accumulation was also responsible for Cu sensitivity in these strains. We showed that exogenous addition of HBA to wild-type cultures sensitized bacteria to Cu to a degree similar to that of a proteasomal degradation mutant. We determined that HBA reduced the production and function of critical Cu resistance proteins of the egulated n opper epressor (RicR) regulon. Furthermore, we extended these Cu-sensitizing effects to an aldehyde that may face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can render susceptible to an existing host defense and could support a broader role for aldehydes in controlling infections. IMPORTANCE is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control 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 susceptibility to copper, an established antibacterial metal used by immune cells to control and other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense.