title: A quinazoline-2,4-diamino analog suppresses Vibrio cholerae flagellar motility by interacting with motor protein PomB and induces envelope stress.
abstract: Vibrio cholerae strains of serogroups O1 and O139, the causative agents of the diarrheal illness cholera, express a single polar flagellum powered by sodium motive force and require motility to colonize and spread along the small intestine. In a previous study, we described a high-throughput assay for screening for small molecules that selectively inhibit bacterial motility and identified a family of quinazoline-2,4-diamino analogs (Q24DAs) that (i) paralyzed the sodium-driven polar flagellum of Vibrios and (ii) diminished cholera toxin secreted by El Tor biotype V. cholerae. In this study, we provide evidence that a Q24DA paralyzes the polar flagellum by interacting with the motor protein PomB. Inhibition of motility with the Q24DA enhanced the transcription of the cholera toxin genes in both biotypes. We also show that the Q24DA interacts with outer membrane protein OmpU and other porins to induce envelope stress and expression of the extracellular RNA polymerase sigma factor σ(E). We suggest that Q24DA-induced envelope stress could affect the correct folding, assembly, and secretion of pentameric cholera toxin in El Tor biotype V. cholerae independently of its effect on motility.
authors.affiliation: Southern Research Institute Drug Discovery Division, Birmingham, Alabama, USA.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Anisia J
authors.initials: AJ
authors.lastname: Silva
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Benitez
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002772:Cholera Toxin / Q000235:genetics / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism; D005407:Flagella / Q000187:drug effects* / Q000502:physiology; D005798:Genes, Bacterial; D017510:Protein Folding; D025941:Protein Interaction Mapping; D011799:Quinazolines / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D014158:Transcription, Genetic; D014734:Vibrio cholerae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; C096349:OmpU protein, Vibrio cholerae; C107541:PomB protein, Vibrio; D011799:Quinazolines; D015222:Sodium Channels; C013474:2,4-diaminoquinazoline; D002772:Cholera Toxin; D012321:DNA-Directed RNA Polymerases