At the Albert Einstein College of Medicine researchers are creating a new methodology for manufacturing antibiotics that don’t develop a pathogen resistance. By targeting a microbe’s ability to infect the body, rather than trying to kill it, the antibiotic doesn’t motivate the pathogen to mutate into a resistant variety.
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 synthesizing 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 fueling quorum sensing.
To design such a compound, the Schramm lab first formed a picture of an enzyme’s transition state — the brief (one-tenth of one-trillionth of a second) period in which a substrate is converted to a different chemical at an enzyme’s catalytic site. (Dr. Schramm has pioneered efforts to synthesize transition state analogs that lock up enzymes of interest. One of these compounds, Forodesine, blocks an enzyme that triggers T-cell malignancies and is currently in a phase IIb pivitol clinical study treating cutaneous T-cell leukemia.)
In the Nature Chemical Biology study, Dr. 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.
"In our lab, we call these agents everlasting antibiotics," said Dr. Schramm. He notes that many other aggressive bacterial pathogens — S. pneumoniae, N. meningitides, Klebsiella pneumoniae, and Staphylococcus aureus — express MTAN and therefore would probably also be susceptible to these inhibitors.
While this study involves three compounds, Dr. Schramm says that his team has now developed more than 20 potent MTAN inhibitors, all of which are expected to be safe for human use: Since MTAN is a bacterial enzyme, blocking it will have no effect on human metabolism.
Press release: Einstein Researchers Develop Novel Antibiotics That Don’t Trigger Resistance
Image: Biofilm formation in pathogenic Vibrio cholerae N16961 cell culture is inhibited by MTAN inhibitor butylthio-DADMe-ImmucillinA (BuT-DADMe-ImmA), biofilm (indicated by white arrows) is visibly reduced in the presence of 1 micromolar inhibitor.