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Design, Synthesis, and Evaluation of Transition-State Analogs as Inhibitors of the Bacterial Quorum Sensing Autoinducer Synthase CepI

preprint
revised on 16.11.2020, 14:13 and posted on 17.11.2020, 05:32 by Erin Higgins, Julian Kellner-Rogers, Alexandra Estanislau, Alec Esposito, Nora R. Vail, Sterling Payne, Julia Stockwell, Scott Ulrich

Quorum sensing is a bacterial signaling system that involves the synthesis and subsequent detection of signal molecules called autoinducers. The main autoinducer in gram-negative bacteria are acylated homoserine lactones, produced by the LuxI family of autoinducer synthase enzymes and detected by the LuxR family of autoinducer receptors. Quorum sensing allows for changes in gene expression and bacterial behaviors in a coordinated, cell density dependent manner. Quorum sensing controls the expression of virulence factors in some human pathogens, making quorum sensing an antibacterial drug target. Here we describe the design and synthesis of transition-state analogs of the autoinducer synthase enzymatic reaction and the evaluation of these compounds as inhibitors of the synthase CepI. One such compound potently inhibits CepI and constitutes a new type of inhibitor against this underdeveloped antibacterial target.


Funding

R15GM131316

History

Email Address of Submitting Author

sulrich@ithaca.edu

Institution

Ithaca College

Country

United States

ORCID For Submitting Author

0000-0002-7117-3684

Declaration of Conflict of Interest

No conflict of interest.

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