Dynamic drug combination methods for suppressing bacterial antibiotics resistance adaptation

Abstract

Staphylococcus aureus (S. aureus) is a common pathogen that can cause high mortality and morbidity. Every year, many people die from S. aureus related infections. Methicillin resistant S. aureus (MRSA) strain is typically responsible for severe and complicated infections in human beings. For this reason it is also considered as one of the "Superbug". It is resistant to many drugs and the glycopeptide vancomycin is the only available antibiotic that is active against MRSA infections. However, recent reports indicate that vancomycin intermediate-resistant MRSA strains are emerging worldwide. Therefore, there is a concern that MRSA would gradually become fullyresistant to vancomycin in the near future and newer treatment strategies or compounds that can effectively cure S. aureus related infections should be well underway before our last antibiotic runs out. Plants have been naturally used since the ancient times as medicine and still many plant compounds can be found in the treatment of major ailments such as malaria and cancer. Due to multi-drug resistance problems in clinical settings and the need for newer compounds, there is great interest in phytochemical research because of their hypothesized and proven antimicrobial activities. Combinations of synergistic phytochemicals and antibiotics are assumed to be a new option to solve the drug resistance problem. Their combination can increase the efficacy and the killing rate and the chance of resistance development can be delayed. In this study, the effects of using conventional antibiotics in combination with phytochemicals were studied by using checker board methods and time-kill assays using 12 S. aureus strains. Studies suggested that tannic acid was synergistic with fusidic acid, minocycline, cefotaxime and rifampicin and additive with ofloxacin and vancomycin. Quercetin showed synergism with minocycline, fusidic acid and rifampicin. In a particular treatment option, the stability of the compounds (drugs or phytochemicals) is important as it selects resistance development in bacteria. The stability and the effectiveness of conventional antibiotics or phytochemicals were studied by inducing single-step adaptive resistant development in MRSA. The duration it took to get phenotypic mutant strains for a particular drug/phytochemical