The urgent need to develop new antibacterials is indisputable, especially for infections resulting from multi- and extensively-drug resistant Gram-negative pathogens. The current arsenal of antibacterials target a limited number of essential enzymes and processes and resistance evolution now outpaces our ability to derivatize known chemotypes and advance the new entities through clinical evaluation. Despite great effort, very few new targets have been identified for Gram-negative bacteria in the last 50 years. In contrast to the dogma that only compounds that completely inhibit cell growth will find clinical utility, one strategy gaining significant traction is to render organisms vulnerable to host immune clearance by targeting virulence determinants or processes that control the expression of pathogenicity. In this context, bacterial two-component signal transduction systems (2CSTS) represent promising targets. Bacterial 2CSTS are conserved across many drug-resistant Gram-negative pathogens, and are known to regulate gene transcription involved in cell growth, envelope integrity, quorum sensing, and expression of virulence factors. As such, modulation of these systems represents a promising antibacterial strategy and is expected to exhibit complementarity to existing approaches. CpxRA is a 2CSTS found in many drug-resistant Gram-negative pathogens and genetic activation of CpxRA abolishes the virulence of a number of pathogens in murine models. Recently, small molecule 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. This poster will present our recent progress towards advancing this chemotype to provide chemical probes poised for utilization in advancing the understanding of the biological significance and therapeutic potential of CpxRA and 2CSTS in general. Results will include a discussion of the stereochemical requirements of this chemotype and the features that drive potency.

First-generation structure-activity relationship studies of 2,3,4,9-tetradhydro-1H-carbazol-1-amines as CpxRA modulators

2019 Spring National Meeting

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