A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis

Scientific Reports
Hongfen YangRobert W Huigens

Abstract

Unlike individual, free-floating planktonic bacteria, biofilms are surface-attached communities of slow- or non-replicating bacteria encased within a protective extracellular polymeric matrix enabling persistent bacterial populations to tolerate high concentrations of antimicrobials. Our current antibacterial arsenal is composed of growth-inhibiting agents that target rapidly-dividing planktonic bacteria but not metabolically dormant biofilm cells. We report the first modular synthesis of a library of 20 halogenated phenazines (HP), utilizing the Wohl-Aue reaction, that targets both planktonic and biofilm cells. New HPs, including 6-substituted analogues, demonstrate potent antibacterial activities against MRSA, MRSE and VRE (MIC = 0.003-0.78 µM). HPs bind metal(II) cations and demonstrate interesting activity profiles when co-treated in a panel of metal(II) cations in MIC assays. HP 1 inhibited RNA and protein biosynthesis while not inhibiting DNA biosynthesis using 3H-radiolabeled precursors in macromolecular synthesis inhibition assays against MRSA. New HPs reported here demonstrate potent eradication activities (MBEC = 0.59-9.38 µM) against MRSA, MRSE and VRE biofilms while showing minimal red blood cell lysis or cytotoxici...Continue Reading

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Citations

Jul 2, 2020·Natural Product Reports·Roberta J MelanderChristian Melander
May 1, 2020·Chembiochem : a European Journal of Chemical Biology·Haraldur Y Juliusson, Snorri Th Sigurdsson
Aug 9, 2019·MedChemComm·Amber M ScharnowWilliam M Wuest
Feb 28, 2019·Chembiochem : a European Journal of Chemical Biology·Robert W HuigensHongfen Yang
Nov 24, 2020·Future Medicinal Chemistry·Robert W Huigens
Jul 22, 2021·Organic & Biomolecular Chemistry·Robert W Huigens IiiShouguang Jin
Aug 30, 2020·Bioorganic & Medicinal Chemistry Letters·Tao XiaoRobert W Huigens
Dec 28, 2017·ACS Infectious Diseases·Heidi WolfmeierRobert E W Hancock
Apr 6, 2019·Journal of Medicinal Chemistry·Yasmeen AbouelhassanRobert W Huigens

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Datasets Mentioned

BETA
BAA-1707

Methods Mentioned

BETA
Antibacterial
fluorescence microscopy
column chromatography
Assay
NMR

Software Mentioned

ImageJ
ChemBioDraw Ultra
Excel

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