A Common Target of Nitrite and Nitric Oxide for Respiration Inhibition in Bacteria

Nitrite and nitric oxide (NO) are well-known bacteriostatic agents with similar biochemical properties. However, many studies have demonstrated that inhibition of bacterial growth by nitrite is independent of NO. Here, with Shewanella oneidensis as the research model because of its unusually high cytochrome (cyt) c content, we identify a common mechanism by which nitrite and NO compromise cyt c biosynthesis in bacteria, and thereby inhibit respiration. This is achieved by eliminating the inference of the cyclic adenosine monophosphate-catabolite repression protein (cAMP-Crp), a primary regulatory system that controls the cyt c content and whose activity is subjected to the repression of nitrite. Both nitrite and NO impair the CcmE of multiple bacteria, an essential heme chaperone of the System I cyt c biosynthesis apparatus. Given that bacterial targets of nitrite and NO differ enormously and vary even in the same genus, these observations underscore the importance of cyt c biosynthesis for the antimicrobial actions of nitrite and NO.