The Purdue College of Pharmacy is pleased to honor and recognize the outstanding research and scholarship generated by our faculty each month. This month we highlight Dr. Daniel Flaherty, associate professor of medicinal chemistry and molecular pharmacology, for his recent publication, “Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to Neisseria gonorrhoeae a-Carbonic Anhydrase”, which can be read in ACS Med Chem Lett. (December, 2022; https://pubmed.ncbi.nlm.nih.gov/36655133/).
The Centers for Disease Control and Prevention (CDC) considers drug-resistant Neisseria gonorrhoeae (N. gonorrhoeae), the bacteria that causes the sexually transmitted disease gonorrhea, as one of the most serious threats to public health among drug-resistant pathogens. Recently, an isolated strain from patients was found to be resistant to all antibiotics commonly used to treat this infection leading to the reality of an untreatable infection.
This study is a small part of a larger research project that Flaherty and his team are tackling to develop new, safe therapeutics to combat this drug-resistant pathogen.
In humans, carbonic anhydrase enzymes have been targeted for decades with FDA-approved drugs for various health conditions. The Flaherty team discovered that bacteria have similar enzymes and that the FDA-approved drugs, as well as new molecules from their lab, inhibit these enzymes in bacteria leading to antibacterial activity. Thus, bacterial carbonic anhydrases are new potential drug targets to treat infections such as those caused by pathogen N. gonorrhoeae.
Flaherty said the goal of this research project is the development of a safe oral treatment for drug-resistant gonorrhea infections. Currently there are no oral antibiotics recommended by the CDC for treatment of gonorrhea with the only recommended treatment being an injectable antibiotic. This study is one stepping-stone on the path to realizing that goal.
“We sought to understand the key binding interactions of the molecule to the enzyme so that we may use this information to design future inhibitors that will inhibit the N. gonorrhoeae carbonic anhydrase and not inhibit the human carbonic anhydrases,” Flaherty said. “This could then lead to potential drugs that inhibit the bacteria but do not have exhibited side-effects in humans due to inhibiting the human carbonic anhydrases.”
This study was the first to provide 3-dimensional structural information, using a technique known as X-ray crystallography, for small molecules bound to the carbonic anhydrase from the bacterial pathogen N. gonorrhoeae. It allows the research team to visualize the key interactions the molecules make with the enzyme and demonstrates key differences in how the molecules interact with the bacterial carbonic anhydrase compared to the human carbonic anhydrase.
“We learned that the molecules bind to the bacterial carbonic anhydrases differently than compared to the related human carbonic anhydrases. We were able to use the 3-dimensional structures to explain the changes in potency for the molecules against the enzyme.”
This study is part of an active project to develop new drugs for the treatment of N. gonorrhoeae infections funded by the National Institutes for Health.
Moving forward the group is focused on taking the best molecules with potency against N. gonorrhoeae and testing how well they clear infection in animal models. The group also has a similar research project for the development of bacterial carbonic anhydrase inhibitors for the treatment of vancomycin-resistant enterococcus, another highly problematic drug-resistant bacterial pathogen.
The laboratory is also pursuing a research project for the development of new strategies to target drug efflux in bacteria, a common resistance mechanism in problematic bacterial pathogens.
Additionally, the group also is involved in development of inhibitors for the human protein adenylyl cyclase type 1 for the treatment of chronic pain conditions in collaboration with the laboratory of Dr. Val Watts in the Department of Medicinal Chemistry and Molecular Pharmacology in the Purdue College of Pharmacy.
The research was conducted by Flaherty; Anil Marapaka, first author and current post-doc; Molly Youse and Katrina Holly, graduate students; Weiwei An, former post-doc; and Alessio Nocentini, Ravi Yadav, Chittaranjan Das, Mohamed Seleem and Claudiu Supuran – all collaborators.