Carbonic Anhydrase Inhibition as a Target for Antibiotic Synergy in Enterococci
Gayatri Shankar Chilambi, Yuhao Wang, Nathan R. Wallace, Chetachukwu Obiwuma, K. Evans, Yanhong Li, M. Shalaby, Daniel P. Flaherty, Ryan K. Shields, Yohei Doi, Daria Van Tyne
Abstract
Enterococcal infections can be difficult to treat, and new therapeutic approaches are needed. In studying an E. faecalis clinical strain from an infected patient, we found that the bacteria were rendered hypersusceptible to aminoglycoside antibiotics through a mutation that disrupted the α-CA. Our follow-on work suggested two different ways that α-CA disruption causes increased gentamicin accumulation in E. faecalis: increased proton motive force-powered uptake and increased membrane permeability. We also found that a mammalian CA inhibitor could sensitize a variety of E. faecalis strains to killing with gentamicin. Given that mammalian CA inhibitors are frequently used to treat conditions such as glaucoma, hypertension, and epilepsy, our findings suggest that these "off-the-shelf" inhibitors could also be useful partner antibiotics for the treatment of E. faecalis infections.