Optimization of a β-Lactam Scaffold for Antibacterial Activity via the Inhibition of Bacterial Type I Signal Peptidase.

Basic Information

ID: ALA4145559

Journal: ACS Med Chem Lett

Title: Optimization of a β-Lactam Scaffold for Antibacterial Activity via the Inhibition of Bacterial Type I Signal Peptidase.

Authors: Yeh CH, Walsh SI, Craney A, Tabor MG, Voica AF, Adhikary R, Morris SE, Romesberg FE.

Abstract: β-Lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). The unparalleled success in their development has inspired efforts to develop them as inhibitors of other targets. Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that β-lactams with the 5S stereochemistry, as opposed to the 5R stereochemistry of the traditional β-lactams, would be required for inhibition. We report the synthesis and evaluation of a variety of 5S penem derivatives and identify several with promising activity against both a Gram-positive and a Gram-negative bacterial pathogen. To our knowledge these are the first 5S β-lactams to possess significant antibacterial activity and the first β-lactams imparted with antibacterial activity via optimization of the inhibition of a target other than a PBP. Along with the privileged status of their scaffold and the promise of bacterial signal peptidase I (SPase) as a target, this activity makes these compounds promising leads for development as novel therapeutics.

CiteXplore: 29670704

DOI: 10.1021/acsmedchemlett.8b00064

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