The compounds work against two notorious microbes: Vibrio cholerae, which causes cholera; and E. coli 0157:H7, the food contaminant.
Most antibiotics initially work extremely well. But through mutation and the selection pressure exerted by the antibiotic, a few bacterial cells inevitably manage to survive, repopulate the bacterial community, and flourish as antibiotic-resistant strains. Vern L. Schramm, senior author of the paper, hypothesised that antibiotics that could reduce the infective functions of bacteria, but not kill them, would minimise the risk that resistance would later develop.
Researchers earlier reported transition state analogues of an enzyme that interferes with "quorum sensing" - the process by which bacteria communicate with each other by producing and detecting signalling molecules known as autoinducers. These autoinducers coordinate bacterial gene expression and regulate processes - including virulence - that benefit the microbial community. Previous studies had shown that bacterial strains defective in quorum sensing cause less-serious infections.
Rather than killing Vibrio cholerae and E. coli 0157:H7, the researchers aimed to disrupt their ability to communicate via quorum sensing. Their target: A bacterial enzyme, MTAN, that is directly involved in synthesising the autoinducers crucial to quorum sensing. Their plan: Design a substrate to which MTAN would bind much more tightly than to its natural substrate - so tightly, in fact, that the substrate analog permanently "locks up" MTAN and inhibits it from fuelling quorum sensing.
In the study, Schramm and his colleagues tested three transition state analogs against the quorum sensing pathway. All three compounds were highly potent in disrupting quorum sensing in both V. cholerae and E. coli 0157:H7. To see whether the microbes would develop resistance, the researchers tested the analogs on 26 successive generations of both bacterial species. The 26th generations were as sensitive to the antibiotics as the first.
MEDICA.de; Source: Albert Einstein College of Medicine