Genetic Dissection of the Fermentative and Respiratory Contributions Supporting Vibrio cholerae Hypoxic Growth.

Both fermentative and respiratory processes contribute to bacterial metabolic adaptations to low oxygen tension (hypoxia). In the absence of O as a respiratory electron sink, many bacteria utilize alternative electron acceptors, such as nitrate (NO). During canonical NO respiration, NO is reduced in a stepwise manner to N by a dedicated set of reductases. , the etiological agent of cholera, requires only a single periplasmic NO reductase (NapA) to undergo NO respiration, suggesting that the pathogen possesses a noncanonical NO respiratory chain. In this study, we used complementary transposon-based screens to identify genetic determinants of general hypoxic growth and NO respiration in We found that while the NO respiratory chain is primarily composed of homologues of established NO respiratory genes, it also includes components previously unlinked to this process, such as the Na-NADH dehydrogenase Nqr. The ethanol-generating enzyme AdhE was shown to be the principal fermentative branch required during hypoxic growth in Relative to single or mutant strains, a strain lacking both genes exhibited severely impaired hypoxic growth and Our findings reveal the genetic basis of a specific interaction between disparate energy production pathways that supports pathogen fitness under shifting conditions. Such metabolic specializations in and other pathogens are potential targets for antimicrobial interventions. Bacteria reprogram their metabolism in environments with low oxygen levels (hypoxia). Typically, this occurs via regulation of two major, but largely independent, metabolic pathways: fermentation and respiration. In this study, we found that the diarrheal pathogen has a respiratory chain for NO that consists largely of components found in other NO respiratory systems but also contains several proteins not previously linked to this process. Both AdhE-dependent fermentation and NO respiration were required for efficient pathogen growth under both laboratory conditions and in an animal infection model. These observations provide a specific example of fermentative respiratory interactions and identify metabolic vulnerabilities that may be targetable for new antimicrobial agents in and related pathogens.