(566c) Chemogenomic Deduction of Escherichia coli's Nitric Oxide Response Network

Nitric oxide (NO) is employed by mammalian immune systems to counter microbial invasions. To elucidate how NO interacts with E. coli's genomic program and induces bacteriostasis, we employed a systems biology approach to identify NO targets and construct the biochemical response network via transcriptome and pathway analysis, NO chemistry, genetics, and biochemical validations. Our approach identified the comprehensive NO-response network in E. coli, and evinced that NO halts bacterial growth via inhibition of branched-chain amino acid (BCAA) biosynthesis. In particular, our analysis indicates that NO inhibits the activity of dihydroxy-acid dehydratase (IlvD), an essential component of isoleucine, leucine, and valine synthesis. As mammals do not synthesize BCAAs, inhibition of IlvD may have served to foster NO's role in the immune arsenal. Furthermore we implicate the global anoxic respiratory control (arc) system in the NO response, and we illustrate that E. coli's general iron-sulfur cluster repair system is an important component of the defense response.