Scientists at EPFL have uncovered the molecular basis behind some of the neurological side effects of sulfonamide antibiotics, providing doctors with possible means to minimize them in patients.
Since the discovery of Prontosil in 1932, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, from acne to chlamydia and pneumonia. However, their side effects can include serious neurological problems like nausea, headache, dizziness, hallucinations and even psychosis. In a recent Science publication, EPFL researchers have shown for the first time how sulfonamides can interfere with a patient’s nervous system.
The problem is that, even though we know how sulfonamides work, we do not understand the actual molecular mechanics behind their side effects. Consequently, it is difficult to modify drug structure or customize therapeutic regimes in order to better serve the needs of patients. That is the critical issue addressed by a team of EPFL scientists led by Kai Johnsson at EPFL’s Laboratory of Protein Engineering (LIP).
The team drew from previous research showing that blocking the activity of a certain enzyme (sepiapterin reductase) affects the levels of an important molecule called tetrahydrobiopterin (BH4) in cells. BH4 is critical for the production of neurotransmitters like serotonin and dopamine, and BH4 deficiency causes similar neurological problems to those associated with sulfonamide side effects.
The EPFL scientists showed for the first time that sulfonamides actually bind to the part of the enzyme that makes BH4. Using a high-throughput drug screening system, the researchers identified ten sulfonamides that strongly inhibit the enzyme. Taking advantage of the expertise of Florence Pojer at EPFL’s Global Health Institute, the scientists were able to solve the enzyme’s molecular structure and determine how sulfonamides bind to it.
Sulfonamides also seem to act on the actual biochemical pathway that synthesizes BH4, as increasing doses of the drugs decreased BH4 concentrations in cultured human cells. The critical finding, however, was that along with BH4, sulfonamides also reduced the actual production of dopamine. By giving cultured human nerve cells different sulfonamides, the researchers found that their natural production of dopamine decreased in proportion to the sulfonamide doses. In addition, it was clear that the impact on dopamine production was different between sulfonamides.
The group’s work shows for the first time that sulfonamides interfere with the biosynthesis of neurotransmitters, which can account for their reported neurological side effects. It also helps us understand how the activity of these drugs relates to their molecular structure, and suggests ways of improving their clinical use.
“Once you know what’s happening you can begin to think about strategies to address the problem – and that is the impact of this work”, says Kai Johnsson. “Historically, I don’t think that there is a more important class of drugs than sulfonamides, and now we can understand them better. It also reminds us that surprising discoveries can be made even for drugs this old.”
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.
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 project represents a collaboration between EPFL’s School of Basic Sciences and School of Life Sciences, and was further supported by the Swiss National Science Foundation (SNSF) and the Swiss National Centre of Competence in Research (NCCR) Chemical Biology, who also provided the high-throughput drug screening system.
Chemical & Engineering News, ISSN 0009-2347, Copyright © 2013 American Chemical Society
- New ideas for old drugs, News Mediacom, EPFL