FDA-Approved Medications with Antibiotic Activity

“Bugs are clever: They can adapt and find ways around the things we develop to kill them. So if we attack them at multiple targets, it’s harder for them to make one little change to get around it,” said Prof. Oldfield.

The researchers were interested in finding uncouplers that sabotage the bacterial energy production line, shutting down cellular processes. Such compounds are already used to treat parasitic infections. Inspired by clofazimine, a leprosy drug now being used to treat tuberculosis, they searched among drugs, that are either already available or in development, to find uncouplers based on the drugs’ known chemical structures. “What we found is that a lot of FDA-approved molecules that are in use actually do kill bacteria and also act as uncouplers,” said Prof. Oldfield, “What’s even better is that some of those molecules also inhibit enzymes specific to bacteria, or disrupt the membrane or the cell wall.”

Such multitarget drugs could have broader applications against an assortment of infections. For example, vacquinol, a compound being developed to treat glioblastoma, a form of brain cancer. The researchers found that, in addition to its uncoupling properties, vacquinol inhibits a key enzyme involved in virulence in tuberculosis bacteria. They then searched for other compounds with similar structures to vacquinol and found compounds that were potent antibiotics against tuberculosis and Staphylococcus aureus.

“It’s a new approach to antibiotics, targeting enzymes together with bacterial energy production,” said Prof. Oldfield.

The researchers hope to develop compounds that are metabolized into uncouplers inside the bacterial cell, further reducing cross-reactivity with human cells and making it more difficult for bacteria to develop resistance. For example, certain heartburn drugs are metabolized within the cell into a compound that acts against tuberculosis. “The whole idea is that it’s possible that some of these compounds that are FDA-approved will work. You can screen a million chemicals to find a new compound but in general you have no idea about its toxicology, or you can start with something that’s known,” said Prof. Oldfield, “Once you start making derivatives, you’ll have to prove they’re safe, but there’s a greater chance to get something that’s safe and effective by starting with an approved drug than if you just go into the chemistry lab and screen unknown compounds.”

The paper, by Feng X et al., was published online ahead of print December 7, 2015, in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

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