The National Institutes of Health (NIH) has awarded Dr. Walter Fast, associate professor of medicinal chemistry at The University of Texas at Austin’s College of Pharmacy, a four-year $2.1 million grant to develop small-molecules that counter antibiotic resistance in Gram-negative bacteria. If successful, the research could lead to new drugs for treating bacterial infections that are resistant to most antibiotics.
Antibiotic resistance occurs when bacteria alters itself to reduce the effectiveness of drugs designed to eliminate bacteria. The most common cause of resistance is overuse of antibiotics. As bacteria are increasingly exposed to antibiotic treatments, they evolve in ways that make them less vulnerable to the treatments. This resistance gives rise to superbugs that do not respond to current antibiotic therapies.
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 since 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, “but there are currently no approved drugs that counter metallo-beta-lactamase activity.”
Fast had studied metallo-beta-lactamases as a postdoctoral fellow, but when he joined the UT Austin faculty in 2002, he moved his focus to structurally related proteins that interfere with interbacterial communication pathways.
“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 resources for the project. Ultimately, the team’s goal is to develop a suite of structurally diverse inhibitors suitable for pre-clinical trials.