The compounds work against two notorious microbes: Vibrio cholerae, which causes cholera; and E. coli 0157:H7, the food contaminant that each year in the U.S. causes approximately 110,000 illnesses and 50 deaths.
Most antibiotics initially work extremely well, killing more than 99.9% of microbes they target. 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, Ph.D., professor and Ruth Merns Chair of Biochemistry at Einstein and senior author of the paper, hypothesized that antibiotics that could reduce the infective functions of bacteria, but not kill them, would minimize the risk that resistance would later develop.
Dr. Schramm's collaborators at Industrial Research Ltd. 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 signaling 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 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.
Other Einstein researchers involved in the study were Jemy Gutierrez, the lead author, Tamara Crowder, Agnes Rinaldo-Matthis, M. C. (Joseph) Ho and Steven C. Almo. The powerful inhibitors were reported in an earlier publication in collaboration with the Carbohydrate Chemistry Team of Industrial Research Ltd., in New Zealand.
The study, "Transition State Analogs of 5' — Methylthioadenosine Nucleosidase Disrupt Quorum Sensing" by Vern L. Schramm et al., appears in the March 8, 2009 online edition of Nature Chemical Biology.
The compounds in this paper have been licensed to Pico Pharmaceuticals, which plans to develop and initiate clinical trials of transition-state analogues. Dr. Schramm is a Pico Pharmaceuticals co-founder and chairman of its scientific advisory board.
Deirdre Branley | EurekAlert!
Further reports about: > Chemical > Chemical Biology > Cholera > E. coli > MTAN > Molecules > Nature Immunology > Pharmaceuticals > Staphylococcus aureus > T-cell > T-cell leukemia > T-cell malignancies > Vibrio vulnificus > antibiotic-resistant strains > bacterial pathogens > bacterial resistance > food contaminant > novel antibiotics > synthetic biology
Lethal combination: Drug cocktail turns off the juice to cancer cells
12.12.2018 | Universität Basel
Smelling the forest – not the trees
12.12.2018 | Universität Konstanz
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...
What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.
Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...
Scientists at the University of Stuttgart and the Karlsruhe Institute of Technology (KIT) succeed in important further development on the way to quantum Computers.
Quantum computers one day should be able to solve certain computing problems much faster than a classical computer. One of the most promising approaches is...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
12.12.2018 | Health and Medicine
12.12.2018 | Physics and Astronomy
12.12.2018 | Health and Medicine