The emergence and spread of resistance to current antibacterial agents is a major public health threat, and there is an urgent need to develop new strategies to address this issue. This study demonstrates a “dimensionally enhanced” (multiplexed) antibacterial activity library screening approach against MRSA. As the first dimension of this approach, we evaluate the use of an <i>in vitro</i> microsomally metabolized FDA approved drug library screen for the discovery of novel anti-MRSA agents. This comparative un-met (UM) vs pre-met (PM) screening strategy allows agents with antibacterial metabolites to be identified. To further enhance the ability of this approach to identify interesting antibacterial activities (second dimension), it was combined with a +/- resistant-to-antibiotic (cefoxitin) screen that allows synergistic (or antagonistic) agents to also be identified. This approach provides an information rich and interesting set of active agents with high translational and clinical potential. Capecitabine was identified as an exemplary drug only active after metabolism, with three identified active anti-MRSA metabolites. This screen also identified several agents with strongly synergistic interactions with cefoxitin. This study illustrates the potential of such a multidimensional screening approach to identify interesting lead agents.<br/>

Metabolism enhanced multiplexed FDA-approved drug screening for novel antibacterial activities

2019 Fall National Meeting

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