SoxRS-mediated lipopolysaccharide modification enhances resistance against multiple drugs in Escherichia coli.
Lipopolysaccharide (LPS) is a major constituent of the outer membrane of gram-negative bacteria that serves as a barrier against harmful molecules, including antibiotics. The waaYZ locus that encodes the LPS core biosynthetic function in Escherichia coli was found to be induced strongly by superoxide generators but not by H(2)O(2), ethanol, or heat shock. This induction was dependent on SoxRS, a superoxide and nitric oxide sensing system, through a soxbox in the waaY promoter that binds SoxS. A DeltawaaYZ mutant became more sensitive to some superoxide generators, and the activation of SoxR by these drugs became more sensitized in the mutant. Through phenotypic microarray analysis, we found that the mutant became sensitive to a wide variety of chemicals not restricted to oxidizing agents. We found that the mutant is under envelope stress and is altered in LPS composition, as monitored by the level of sigma(E) activation and changes in the electrophoretic mobility of LPS, respectively. waaY expression was also regulated by MarA (multiple-antibiotic resistance regulator), which shares a binding site (soxbox) with SoxS, and was induced by salicylate, a nonoxidative compound. These results demonstrate a novel way of protecting gram-negative bacteria against various compounds by modifying LPS, possibly through phosphorylation. Since either oxidant or nonoxidant compounds elicit resistance toward themselves and other toxic drugs, this mechanism could serve as an efficient way for pathogenic bacteria to enhance survival during antibiotic treatment within an oxidant-rich host immune environment.
Lee
Joon-Hee
JH
Department of Pharmacy, Laboratory of Microbiology, College of Pharmacy, Pusan National University, Busan, South Korea. joonhee@pusan.ac.kr
Lee
Kang-Lok
KL
Yeo
Won-Sik
WS
Park
Su-Jin
SJ
Roe
Jung-Hye
JH
D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D015152:Blotting, Northern; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000502:physiology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D005816:Genetic Complementation Test; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology; D010269:Paraquat / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D024483:Vitamin K 3 / Q000494:pharmacology
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D008070:Lipopolysaccharides; C080002:MarA protein, E coli; D009285:Naphthoquinones; D015534:Trans-Activators; D014157:Transcription Factors; C472372:WaaZ protein, E coli; C070724:SoxR protein, Bacteria; C070725:SoxS protein, E coli; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D010269:Paraquat; C014758:plumbagin