Novel classes of antibacterial agents are urgently needed due to increasing bacterial resistance against the current standards of care in both hospital and community settings. Toward this end, a high throughput cell-based SOS reporter screen utilizing an E. coli ?tolC cell line was developed to identify inhibitors of DNA metabolism and replication. Following the screening of AstraZeneca's corporate deck, a biarylcyclohexylacetic acid that triggered an SOS response was identified for additional work and profiling. Optimization of the hit and isolation of resistant mutants against this class of compounds in H. influenzae identified the target as DNA gyrase. This talk will cover the SAR and target identification work undertaken to identify the mode of action for the series. 

Novel inhibitors of bacterial DNA gyrase identified by a high throughput phenotypic screen of bacterial SOS response

248th National Meeting (2014)

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