Dimensionally Enhanced Antibacterial Library Screening.
ACS Chem Biol. 2019 Nov 01;:
Authors: Ayon NJ, Gutheil WG
The emergence and spread of antimicrobial resistance is a major public health threat, and there is an urgent need to develop new strategies to address the issue. In this study, the possibility of enhancing a whole cell based antibacterial library screen by increasing the dimensionality of the screening effort is explored using methicillin resistant Staphylococcus aureus (MRSA) as the target organism. One dimension involved generating and screening a human liver microsome metabolized FDA approved drug library. Comparative screening of the un-metabolized (UM) and pre-metabolized (PM) libraries allows identification of intrinsically active agents from the UM library screen, and of agents with active metabolites from the PM library screen. To further enhance this screening effort, it was combined with a -/+ resistant to antibiotic screen (-/+ cefoxitin; Cef). This allows the identification of agents that can act synergistically with the resistant to antibiotic. This approach revealed 5 compounds with substantially improved activity after metabolism, and 4 compounds with substantial synergistic activity with cefoxitin. Capecitabine in particular only had significant antibacterial activity after metabolism. Its metabolites were isolated, identified and characterized for spectrum of activity along with several other anticancer drugs with anti-MRSA activity. Floxuridine, gemcitabine, novobiocin and rifaximin were identified as having substantial synergy with cefoxitin from the -/+ Cef screens. Checkerboard assays verified synergy for these agents. Floxuridine demonstrated a particularly high degree of synergy with cefoxitin (FIC=0.14). This study demonstrates how a dimensionally enhanced comparative screening effort can identify new antibacterial agents and strategies for countering antibacterial agent resistance.
PMID: 31675203 [PubMed - as supplied by publisher]