Activity of the Lactate Dehydrogenase Inhibitor Oxamic Acid against the Fermentative Bacterium Streptococcus mitis/oralis: Bactericidal Effects and Prevention of Daptomycin Resistance In Vitro and in an Ex Vivo Model

Authors

Razieh Kebriaei, Eugene Applebaum College of Pharmacy and Health Sciences
Arnold S. Bayer, University of California, Los Angeles
Christian K. Lapitan, UCLA Medical Center
Michael J. Rybak, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University
Greg A. Somerville, University of Nebraska-LincolnFollow
Nagendra N. Mishra, University of California, Los Angeles

Document Type

Article

Date of this Version

10-13-2022

Citation

Kebriaei, R.; Bayer, A.S.; Lapitan, C.K.; Rybak, M.J.; Somerville, G.A.; Mishra, N.N. Activity of the Lactate Dehydrogenase Inhibitor Oxamic Acid against the Fermentative Bacterium Streptococcus mitis/oralis: Bactericidal Effects and Prevention of Daptomycin Resistance In Vitro and in an Ex Vivo Model. Antibiotics 2022, 11, 1409. https://doi.org/10.3390/ antibiotics11101409

Comments

Open acces.

Abstract

Streptococcus mitis/oralis is a fermentative bacterium that relies on lactate dehydrogenase to balance its redox poise and keep glycolysis active. Metabolomic analysis of an in vitro– derived daptomycin-resistant (DAP-R) S. mitis/oralis strain (351-D10) revealed differences in glucose catabolism relative to its DAP-susceptible (DAP-S) parental strain, 351. Metabolic changes associated with the transition to this DAP-R phenotype suggested that inhibiting glycolysis could alter DAP susceptibility. In addition, the strong reliance of S. mitis/oralis on glycolysis for energy and biosynthetic intermediates suggested that inhibiting glycolysis would adversely affect growth and biomass accumulation. To test these hypotheses, we used the lactate dehydrogenase inhibitor oxamic acid (OXA) to assess its efficacy against DAP-S S. mitis/oralis strain 351 during DAP exposures in vitro and ex vivo. As expected, OXA was growth inhibitory to S. mitis/oralis in a dose-dependent manner in vitro; however, it did not alter in vitro DAP susceptibility profiles. In contrast, OXA did prevent the emergence of DAP-R in an ex vivo model of simulated endocardial vegetations. These data suggest that metabolic inhibitors directed against this fermentative bacterium with limited metabolic capabilities could enhance killing and potentially forestall the emergence of DAP resistance.