Mentor: Robert J. Kerns, PhD

Year Entered Into Program: 2016

Terminal Degree(s) Received: PhD 2021

Research Description

Chemical probes of efflux mediated bacterial resistance to quinolone class antibiotics

There is an urgent need for new antibiotics capable of treating antibiotic resistant Neisseria gonorrhoeae, the Gram-negative bacterium responsible for gonorrhea. Resistance has emerged to every antibiotic recommended to treat gonorrhea. Prior to 2007, the fluoroquinolone ciprofloxacin was the most commonly used treatment for gonorrhea. Ciprofloxacin and other fluoroquinolones are bacterial type II topoisomerase inhibitors. Target mediated resistance to fluoroquinolones involves disrupting the magnesium-water bridge between the fluoroquinolone and topoisomerase. Quinazoline 2,4 diones (diones) are type II topoisomerase inhibitors that have the same binding mode as fluoroquinolones, but do not rely on a magnesium water bridge. Diones are equipotent in fluoroquinolone-resistant and wild-type topoisomerases. Diones are also excellent substrates for bacterial efflux pumps. As a result, many bacterial species have a level of natural efflux mediated resistance to diones. The Kerns lab has previously demonstrated that fluoroquinolone C7 dimers overcome efflux mediated bacterial resistance and act with potency equal to or greater than fluoroquinolone monomers. I am currently synthesizing dione dimers that are expected to overcome both target-mediated and efflux mediated resistance.

Awards

• Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2017-2019