Attenuating the Streptococcus pneumoniae Competence Regulon Using Urea-Bridged Cyclic Dominant-Negative Competence-Stimulating Peptide Analogs

Muralikrishna Lella, Myung Whan Oh, Shanny Hsuan Kuo, Gee W. Lau, Yftah Tal-Gan

Research output: Contribution to journalArticlepeer-review

Abstract

Streptococcus pneumoniae (pneumococcus) is a prevalent human pathogen that utilizes the competence regulon quorum sensing circuitry to acquire antibiotic resistance and initiate its attack on the human host. Therefore, targeting the competence regulon can be applied as an anti-infective approach with minimal pressure for resistance development. Herein, we report the construction of a library of urea-bridged cyclic dominant-negative competence-stimulating peptide (dnCSP) derivatives and their evaluation as competitive inhibitors of the competence regulon. Our results reveal the first pneumococcus dual-action CSPs that inhibit the group 1 pneumococcus competence regulon while activating the group 2 pneumococcus competence regulon. Structural analysis indicates that the urea-bridge cyclization stabilizes the bioactive α-helix conformation, while in vivo studies using a mouse model of infection exhibit that the lead dual-action dnCSP, CSP1-E1A-cyc(Dab6Dab10), attenuates group 1-mediated mortality without significantly reducing the bacterial burden. Overall, our results pave the way for developing novel therapeutics against this notorious pathogen.

Original languageEnglish (US)
Pages (from-to)6826-6839
Number of pages14
JournalJournal of Medicinal Chemistry
Volume65
Issue number9
Early online dateApr 22 2022
DOIs
StatePublished - May 12 2022

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

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