Chapter 13 : The Nexus of Oxidative Stress Responses and Antibiotic Resistance Mechanisms in and

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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 , leading to transcriptional induction of the 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 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 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 strain (St46) that developed ciprofloxacin resistance during antibiotic therapy were examined. Analyzing the regulatory mechanisms of and 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.

Citation: Demple B. 2005. The Nexus of Oxidative Stress Responses and Antibiotic Resistance Mechanisms in and , p 191-197. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch13
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Figure 1

Control and phenotypic output in the soxRS system. Both latent and activated forms of SoxR protein bind tightly to a site between the −10 and −35 motifs of the soxS promoter. Through its 2Fe-2S iron-sulfur centers, the transcription activating function of SoxR is triggered either by oxidative stress signals generated by redox-cycling agents such as MD or paraquat (resulting in oxidation) or by exposure to nitric oxide (resulting in nitrosylation of the centers). The increased expression of SoxS protein increases its occupancy of binding sites in the target promoters of the regulon, where it recruits σ70 RNA polymerase to activate transcription. The activated genes increased resistance to oxidative stress (e.g., superoxide dismutase) and antibiotics (e.g., micF RNA). Adapted from reference 37.

Citation: Demple B. 2005. The Nexus of Oxidative Stress Responses and Antibiotic Resistance Mechanisms in and , p 191-197. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch13
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Image of Figure 2
Figure 2

A conserved DNA binding domain in the Rob, SoxS, MarA, and AraC proteins. Rob protein secondary structure (27) is shown below an alignment of the E. coli Rob, SoxS, MarA, and AraC proteins. A common domain of ∼100 residues is shared in all the proteins, while Rob has an additional 170 C-terminal residues, probably involved in modulating its transcription-activating function (see text). The first helix-turn-helix motif directly contacts specific DNA sequences; the second shows different secondary contacts in the Rob-DNA structure (27) compared to a MarA-DNA complex (38). The shaded residues correspond to conserved buried hydrophobic residues or contact residues in the DNA binding motifs (27). Adapted from reference 27.

Citation: Demple B. 2005. The Nexus of Oxidative Stress Responses and Antibiotic Resistance Mechanisms in and , p 191-197. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch13
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