The nexus of oxidative stress responses and antibiotic resistance mechanisms in escherichia coli and salmonella

This chapter discusses the mechanistic overlap between seemingly separate regulatory systems, one responding to oxidative stress, the other governing antibiotic resistance mechanisms encoded in the bacterial chromosome. Oxidative stress signals activate SoxR, leading to transcriptional induction of the soxS gene. The overlap in specificity between the two systems (activation of both oxidative stress and antibiotic resistance genes) is embodied in the second-stage regulators, SoxS and MarA. These small proteins are homologous to the C-terminal domain of the AraC/XylS family of transcription activators. For the soxRS regulon , oxidative stress imposed by superoxide-generating agents or macrophagegenerated nitric oxide are the predominant known activation signals. In the absence of oxidative stress, competition of the mutant SoxR in St46 by the nonactivated wild-type protein effectively shut down soxS expression and thus antibiotic resistance. The convergence of different regulatory systems on both oxidative stress and antibiotic resistance genes was unexpected. In another collaboration with Stuart Levy, the properties of a Salmonella enterica strain (St46) that developed ciprofloxacin resistance during antibiotic therapy were examined. Analyzing the regulatory mechanisms of soxRS and marRAB and their roles in resistance to multiple antibiotics proved to be an exciting adventure. The clear relevance of this work to human health was a bonus, as was the chance to learn about whole new areas of research.