By Marissa Shapiro
Neil Osheroff, professor of biochemistry and medicine, is part of an international research collaboration resulting in what is on track to be the first new antibiotic treatment for uncomplicated urinary tract infections or uUTIs in more than 20 years. “We now have a direct path connecting the work conducted in our lab to improving human health,” said Osheroff, who holds the John Coniglio Chair in Biochemistry. “A new antibiotic will come on the market and be used by people who have serious infections, in part because of what we did in this lab. To be able to say we are one of the lead research groups working on this is why I am at Vanderbilt and why I am a biochemist.”
The antibiotic, gepotidacin, completed enrollment in phase III trials ahead of schedule based on an analysis of its efficacy and safety. GSK, the global biopharma company conducting the trials, is working with the Food and Drug Administration on a new drug application for the antibiotic. Gepotidacin inhibits bacterial DNA replication by a distinct mechanism of action determined by Osheroff’s lab that is foundational to GSK’s FDA application.
“Uncomplicated urinary tract infections are the most common outpatient infection with over half of all women developing a uUTI during their lifetime and more than a quarter of women suffering from recurrent uUTIs,” said Chris Corsico, senior vice president and head of development at GSK. “There has been no new class of oral antibiotics for uUTI for over 20 years. With the number of uUTIs caused by [resistant] bacteria increasing, new antibiotic treatments are necessary.”
Current antibiotics like Cipro (ciprofloxacin) are within a drug type called fluoroquinolones, some of the most widely prescribed antibacterials in the world. “The problem with fluoroquinolones is that we’re seeing antibacterial resistance, including specific mutations within enzymes, that makes the drug not interact with infection the way we want,” Osheroff said.
Fluoroquinolones affect two enzymes, but only one mutation in the bacterial DNA can be enough to cause antibiotic resistance. Gepotidacin targets two enzymes that share responsibility in attacking bacterial DNA. This means that bacteria would have to mutate at two spots at exactly the same time to become resistant to this new antibiotic.
“Antibacterial resistance is significantly more difficult with this approach,” Osheroff said. Osheroff, along with former graduate student and current senior research investigator at Bristol Myers Squibb Elizabeth Gibson, and postdoctoral researcher Alexandria Oviatt, successfully worked to target the two enzymes that attack bacterial cells. “Our work in the Osheroff lab becomes even more impactful knowing it can help a new oral antibacterial class come to market,” Gibson said. “During my pharmacy training, it wasn’t uncommon to see patients come back to the pharmacy week after week to fill a new antibacterial prescription to find one to clear up an infection (especially UTIs). Knowing a part of my graduate school work played a small part in combating antimicrobial resistance, a worldwide problem, continues to motivate my work in drug development to help improve patient quality of life.”