Abstract

Mutant selection window (MSW) is the antimicrobial concentration ranging from the minimum inhibitory concentration (MIC) to the mutant prevention concentration (MPC). Placing antibiotic concentration in the MSW is expected to selectively enrich mutant subpopulations while placing the concentration above the window is expected to restrict the selective enrichment of resistant bacteria. Even though there is a rise of multidrug resistant bacteria, there are not many new antibiotics introduced to market in the recent years. Therefore, there is a need to utilize existing knowledge on antibiotics to prevent the development of multidrug resistance and if possible reposition the antibiotics. The increase in knowledge on MSW and microbial evolution of resistance can be of potential use in novel dosing regimens and antimicrobial combinations. In this study, we investigated the effect of the addition of ethyl gallate (EG) on the MSW and MPC of MRSA ATCC strain 43300, before and after it has been induced to develop resistance to tetracycline and fusidic acid. It is observed that tetracycline has narrower MSW than fusidic acid. This suggests that fusidic acid provides less genetic stability than tetracycline and hence it is easy for mutants to develop. We also report that addition of ethyl gallate at 1024μg/ml closes the mutant selection window (i.e. MIC = MPC) of both tetracycline and fusidic acid, thus helping overcome the effect of resistance developed over time. Hence, we propose that combination of ethyl gallate with antibiotics has potential clinical implications and needs further exploration.

Keywords: Ethyl gallate, MRSA, Combination, MSW, MPC, MIC, CFU/ml, mutations, pharmacokinetic, Staphylococcus aureus, ointments, Phenotypes, fusidic acid, tetracycline, antibiotics, linezolid, vancomycin, tigecycline, mupirocin