Dr. Walter Fast, associate professor of medicinal chemistry at The University of Texas at Austin’s College of Pharmacy, has been awarded a four-year $2.1 million grant from the National Institutes of Health (NIH) to develop small-molecules that counter antibiotic resistance in Gram-negative bacteria. If successful, the research could lead to new drugs for clinicians to use in treating bacterial infections that are resistant to most antibiotics.
Fast is studying a class of enzymes, called metallo-beta-lactamases, that confer resistance to almost all clinically-used beta-lactam antibiotics, including penicillins, cephalosporins, and even carbapenems that are often used as ‘drugs of last resort’ for treating resistant infections. One of the more prominent examples is a ‘superbug’ called NDM, named after its primary resistance determinant New Delhi metallo-beta-lactamase, which has quickly spread worldwide after its 2008 discovery in India.
“Inhibitors of these enzymes could resurrect our ability to use a whole class of antibiotics on resistant infections” Fast said, adding “but there are currently no approved drugs that counter metallo-beta-lactamase activity.”
Fast had studied metallo-beta-lactamases as a postdoctoral fellow, but moved his focus to structurally related proteins that interfere with interbacterial communication pathways when he joined the UT Austin faculty in 2002, on-going work that is currently funded by a National Science Foundation grant.
“After hearing about NDM on the news,” said Fast “I felt like we could build on what we’ve learned from related proteins and really make a meaningful contribution.”
He recruited an interdisciplinary research team with labs headed by Dr. Seth Cohen at the University of California, San Diego; Dr. Robert Bonomo at Case Western Reserve University; and Drs. Michael Crowder, David Tierney and Rick Page at the University of Miami, Ohio. The teams use fragment-based library design, high-throughput screening, enzymology, biophysical characterization, X-ray crystallography and microbiology to develop drug-like inhibitors that target the most clinically prevalent metallo-beta-lactamases. The Center for Infectious Disease and the small-molecule screening core of the Texas Screening Alliance at The University of Texas at Austin will also provide important resources for the project. Ultimately, the team’s goal is to develop a suite of structurally diverse inhibitors suitable for pre-clinical trials.