Enhanced Activity against Multidrug-Resistant Bacteria through Coapplication of an Analogue of Tachyplesin i and an Inhibitor of the QseC/B Signaling Pathway

Rilei Yu, Jiayi Wang, Lok Yan So, Peta J. Harvey, Juan Shi, Jiazhen Liang, Qin Dou, Xiao Li, Xiayi Yan, Yen Hua Huang, Qingliang Xu, Quentin Kaas, Ho Yin Chow, Kwok Yin Wong, David J. Craik, Xiao Hua Zhang, Tao Jiang, Yan Wang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

4 Citations (Scopus)

Abstract

Tachyplesin I (TPI) is a cationic β-hairpin antimicrobial peptide with broad-spectrum, potent antimicrobial activity. In this study, the all d-amino acid analogue of TPI (TPAD) was synthesized, and its structure and activity were determined. TPAD has comparable antibacterial activity to TPI on 14 bacterial strains, including four drug-resistant bacteria. Importantly, TPAD has significantly improved stability against enzymatic degradation and decreased hemolytic activity compared to TPI, indicating that it has better therapeutic potential. The induction of bacterial resistance using low concentrations of TPAD resulted in the activation of the QseC/B two-component system. Deletion of this system resulted in at least five-fold improvement of TPAD activity, and the combined use of TPAD with LED209, a QseC/B inhibitor, significantly enhanced the bactericidal effect against three classes of multidrug-resistant bacteria.

Original languageEnglish
Pages (from-to)3475-3484
Number of pages10
JournalJournal of Medicinal Chemistry
Volume63
Issue number7
DOIs
Publication statusPublished - 9 Apr 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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