mechanism of sulfa drugs

Sulfa antibiotics were first used in the 1930s and they revolutionized medicine. A few years later, bacteria began to develop resistance to drugs, and eventually, penicillin replaced them as first-line treatment. Although antibiotic resistance remains a problem with such antibiotics, sulfonamides are still commonly used to treat a variety of bacterial infections.

Sulfonamides act by binding to and inhibiting specific enzymes known as dihydropteroate synthetase (DHPS). This enzyme is essential for the synthesis of folic acid, an essential nutrient. Mammals get folic acid from their diet, but bacteria must synthesize it. Folic acid synthesis requires a chemical reaction between the two molecules DHPP and PABA catalyzed by DHPS.

Bacteria resistant to sulfonamides typically have mutations in the DHPS enzyme. These mutations occur on two floppy rings near the active site of the enzyme. Previous studies have described most of the structure of DHPS, but the structure of floppy disks, highly conserved rings, remains elusive. In addition, the researchers did not know how chemical reactions occur between DHPP and PABA.

A team of scientists led by Dr. Stephen White of St. Jude Children's Research Hospital set out to determine the loop structure and chemical reactions that DHPS helped. Their research was published in the March 2, 2012 issue of Science, funded primarily by the NIH National Institute of Allergy and Infectious Diseases (NIAID).

The scientists isolated DHPS enzymes from two species of bacteria: Bacillus anthracis causing anthrax and Yersinia pestis causing plague. Scientists have embedded DHPP and PABA in the crystals of the enzyme. They then used X-ray crystallography to find high-resolution structures of these molecules at different stages of the chemical reaction.

The researchers found that two floppy rings wrap around PABA early and keep the molecules in place. A chemical reaction occurs between the PABA and DHPP moieties, and then the ring releases the chemical reaction product. This structure also reveals the exact chemical reaction steps that take place between PABA and DHPP.

Sulfa antibiotics work because they are suitable for the active site of DHPS and occupy the location of PABA. By embedding sulfa antibiotics in the crystals of the enzyme, the scientists found that the sulfonamides were fixed by a soft ring structure. However, a small portion of the drug protrudes from the binding pocket. The researchers found that DHPS mutations in drug-resistant bacteria occurred near this small extension.