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Infect. Immun. doi:10.1128/IAI.01557-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Role of RppA in the regulation of polymyxin B susceptibility, swarming, and virulence factor expression in Proteus mirabilis

Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology; and Graduate Institute of Microbiology; College of Medicine, National Taiwan University, and Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China
Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology; and Graduate Institute of Microbiology; College of Medicine, National Taiwan University, and Department of Laboratory Medicine; National Taiwan University Hospital, Taipei, Taiwan, Republic of China

^* To whom correspondence should be addressed. Email: sjliaw{at}ntu.edu.tw.

	Abstract

Proteus mirabilis, a human pathogen that frequently causes urinary tract infection, is intrinsically highly resistant to cationic antimicrobial peptides, such as polymyxin B (PB). To explore the mechanisms underlying P. mirabilis resistance to PB, a mutant which displayed increased sensitivity to PB (over160-fold) was identified by transposon mutagenesis. The mutant was found to have Tn5 inserted in a novel gene rppA. Sequence analysis indicated that rppA may encode a response regulator of the two-component system and was located upstream of the rppB gene, which may encode a membrane sensor kinase. The rppA-knockout mutant of P. mirabilis had an altered lipopolysaccharide (LPS) profile. The LPS purified from the rppA-knockout mutant could bind more PB than that purified from the wild-type. These properties of the rppA-knockout mutant may contribute to its PB-sensitive phenotype. The rppA-knockout mutant exhibited higher swarming motility and cytotoxic activity, and expressed higher levels of flagellin and hemolysin than did the wild-type, suggesting that RppA negatively regulates swarming, hemolysin expression, and cytotoxic activity in P. mirabilis. PB could modulate LPS synthesis/modification, swarming, hemolysin expression, and cytotoxic activity in P. mirabilis through an RppA-dependent pathway, suggesting that PB could serve as a signal to regulate RppA activity. Finally, we demonstrated that the expression of rppA was up-regulated by low-concentration of PB and down-regulated by high concentration of Mg²⁺. Together, these data highlight the essential role of RppA in regulating PB susceptibility and virulence functions in P. mirabilis.

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