The Vibrio cholerae ToxR-regulated porin OmpU confers resistance to antimicrobial peptides.
BPI (bactericidal/permeability-increasing) is a potent antimicrobial protein that was recently reported to be expressed as a surface protein on human gastrointestinal tract epithelial cells. In this study, we investigated the resistance of Vibrio cholerae, a small-bowel pathogen that causes cholera, to a BPI-derived peptide, P2. Unlike in Escherichia coli and Salmonella enterica serovar Typhimurium, resistance to P2 in V. cholerae was not dependent on the BipA GTPase. Instead, we found that ToxR, the master regulator of V. cholerae pathogenicity, controlled resistance to P2 by regulating the production of the outer membrane protein OmpU. Both toxR and ompU mutants were at least 100-fold more sensitive to P2 than were wild-type cells. OmpU also conferred resistance to polymyxin B sulfate, suggesting that this porin may impart resistance to cationic antibacterial proteins via a common mechanism. Studies of stationary-phase cells revealed that the ToxR-repressed porin OmpT may also contribute to P2 resistance. Finally, although the mechanism of porin-mediated resistance to antimicrobial peptides remains elusive, our data suggest that the BPI peptide sensitivity of OmpU-deficient V. cholerae is not attributable to a generally defective outer membrane.
Mathur
Jyoti
J
Department of Immunology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, and Howard Hughes Medical Institute, Boston, Massachusetts 02111, USA.
Waldor
Matthew K
MK
D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D001798:Blood Proteins / Q000737:chemistry* / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008565:Membrane Proteins; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014734:Vibrio cholerae / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity
D018829:Adhesins, Bacterial; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D001798:Blood Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C096349:OmpU protein, Vibrio cholerae; D010455:Peptides; D014157:Transcription Factors; C021623:bactericidal permeability increasing protein; C499324:toxR protein, Vibrio cholerae; C066719:toxR protein, bacteria