LpxC is a Zn-dependent metalloenzyme that catalyzes the first committed step in the biosynthetic pathway of LPS, an essential outer membrane component of Gram negative bacteria.  Many LpxC inhibitors contain a hydroxamate warhead or other chelating moiety, which may bind to unintended metalloenzymes such as Histone DeACetylases (HDACs).  One of our lead series of LpxC inhibitors demonstrated potent antimicrobial activity against Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae, but also showed in vitro inhibition of most classes of HDACs.  Modeling supported the hypothesis that substitution would sterically block HDAC binding and maintain LpxC activity.  Reduced HDAC inhibition by incorporation of this substitution while preserving antimicrobial activity was confirmed experimentally.  Additional compounds with this substitution also exhibited selectivity to LpxC.

Structure-based design of LpxC inhibitors selective against histone deacetylase

246th National Meeting (2013)

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