If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.


Biological Chemistry

Antibiotic Side Effects Explained

Structural Biology: Sulfonamide drugs may harm nervous systems by inhibiting an enzyme

by Sarah Everts
May 24, 2013 | A version of this story appeared in Volume 91, Issue 21

Credit: Science
Many sulfonamide drugs, such as sulfapyridine (pink), inhibit the enzyme sepiapterin reductase (blue), shown with a cofactor (green).
This is a ribbon structure of an enzyme with sulfa drugs interacting with it.
Credit: Science
Many sulfonamide drugs, such as sulfapyridine (pink), inhibit the enzyme sepiapterin reductase (blue), shown with a cofactor (green).

The discovery of sulfonamide antibiotics in the 1930s revolutionized medicine. They were the first synthetic drugs that could cure a battery of bacterial infections. Yet despite more than 70 years of in-depth analysis of the sulfonamide family, researchers have only now discovered a cause for some of the drugs’ more problematic side effects (Science 2013, DOI: 10.1126/science.1232972).

These side effects, along with growing bacterial resistance, have driven many sulfonamide drugs out of favor. But some, such as sulfamethoxazole, remain popular for treating certain kinds of microbial infections such as Pneumocystis pneumonia, says chemical biologist Kai Johnsson of the Swiss Federal Institute of Technology, Lausanne, who led the group reporting the new findings.

Learning the molecular reason behind the side effects might breathe new life into the old drug family. Researchers could modify therapies so patients avoid the headaches, tremors, nausea, vomiting, and insomnia associated with sulfonamides, he says.

The researchers found that a core sulfonyl coupled to an amine, part of the basic architecture of all sulfonamide drugs, slips neatly into the active site of an enzyme called sepiapterin reductase. This enzyme takes part in the biosynthesis of tetrahydrobiopterin, a compound essential to making several neurotransmitters. Sulfonamides disrupt the enzyme’s part in this process, and Johnsson’s team showed that in cell-based assays the interference eventually depletes these neurotransmitters. This could cause the neurological side effects, Johnsson says.

The new work also proposes why one sulfonamide drug, sulfamethazine, does not cause such effects: It has two methyl groups on a heterocyclic ring that make it difficult for the molecule to fit into the enzyme’s active site. Without the methyl groups, the molecule, now called sulfadiazine, can inhibit the enzyme 370 times better.

The work is “a great new twist on an old drug family,” comments Stephen White, a structural biologist who studies sulfonamide resistance at St. Jude Children’s Research Hospital, in Memphis. “In theory, you could redesign sulfa drugs so they don’t fit in sepiapterin reductase,” he says. More realistically, he adds, clinicians could consider giving people supplements to replace neurotransmitter molecules lost by inhibiting the enzyme.



This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.