Targeting the replication initiator of the second Vibrio chromosome: towards generation of vibrionaceae-specific antimicrobial agents.
The Vibrionaceae is comprised of numerous aquatic species and includes several human pathogens, such as Vibrio cholerae, the cause of cholera. All organisms in this family have two chromosomes, and replication of the smaller one depends on rctB, a gene that is restricted to the Vibrionaceae. Given the increasing prevalence of multi-drug resistance in pathogenic vibrios, there is a need for new targets and drugs to combat these pathogens. Here, we carried out a high throughput cell-based screen to find small molecule inhibitors of RctB. We identified a compound that blocked growth of an E. coli strain bearing an rctB-dependent plasmid but did not influence growth of E. coli lacking this plasmid. This compound, designated vibrepin, had potent cidal activity against V. cholerae and inhibited the growth of all vibrio species tested. Vibrepin blocked RctB oriCII unwinding, apparently by promoting formation of large non-functional RctB complexes. Although vibrepin also appears to have targets other than RctB, our findings suggest that RctB is an attractive target for generation of novel antibiotics that only block growth of vibrios. Vibrio-specific agents, unlike antibiotics currently used in clinical practice, will not engender resistance in the normal human flora or in non-vibrio environmental microorganisms.
Yamaichi
Yoshiharu
Y
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA.
Duigou
Stéphane
S
Shakhnovich
Elizabeth A
EA
Waldor
Matthew K
MK
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000187:drug effects*; D002876:Chromosomes, Bacterial / Q000235:genetics*; D004265:DNA Helicases / Q000187:drug effects*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D015534:Trans-Activators / Q000187:drug effects*; D014737:Vibrionaceae / Q000235:genetics*
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D015534:Trans-Activators; C045264:replication initiator protein; D004265:DNA Helicases