Researchers from St. Jude Children’s Research Hospital have determined, at an atomic level, the mechanism used by sulfa drugs to kill bacteria. Such findings may pave the way for the development of new antibiotics that may be harder for bacteria to resist and have fewer side effects.
The researchers focused on dihydropteroate synthase (DHPS), which most disease-causing microorganisms need to make folate, which is required for the production of DNA and some amino acids. The researchers, led by Stephen White, PhD, chair of the St. Jude Department of Structural Biology and corresponding author on the paper about the study published in Science, worked with gram negative and positive bacteria to delve into the production of DHPS on the molecular level. Sulfa drugs target DHPS, which could enable the researchers to target mechanisms of resistance at a key level and improve the efficacy of sulfa drugs.
Sulfa drugs were first developed in the 1930s. According to the authors, even though they were early victims of resistance, they are still used to combat emerging infectious diseases and in patients with weakened immune systems. According to study co-author Richard Lee, PhD, a member of the St. Jude Department of Chemical Biology and Therapeutics, the growing problem of antibiotic resistance has led to a renewed interest in sulfa drugs.
"The structure we found was totally unexpected and really opens the door for us and others to design a new class of inhibitors targeting DHPS that will help us avoid side effects and other problems associated with sulfa drugs," Dr. White adds.
The study also showed that the binding sites of pABA and the sulfa drugs overlap, but that sulfa drugs extend beyond the pocket in which pABA binds. Because mutations associated with drug resistance cluster around this extended region of the pABA pocket, this additional finding could explain how mutations can prevent the drugs from binding without seriously affecting the binding of pABA. According to the researchers, the study also highlights the transitory structure made by the two DHPS loops as a target for new drugs that would be difficult for bacteria to develop resistance against.
"This is a key finding for drug discovery because it reveals chemical features of the DHPS enzyme's active site that we can exploit in developing new drugs," says co-author Donald Bashford, PhD, an associate member of the St. Jude Department of Structural Biology.
— Julia Ernst, MS, Assistant Editor
