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  • A drug candidate for Alzheimer's and Huntington's disease, PBT2, can be repurposed to render Neisseria gonorrhoeae susceptible to natural cationic antimicrobial peptides.

    Author(s)
    Jen, Freda E-C
    El-Deeb, Ibrahim M
    Zalucki, Yaramah M
    Edwards, Jennifer L
    Walker, Mark J
    von Itzstein, Mark
    Jennings, Michael P
    Griffith University Author(s)
    von Itzstein, Mark
    Jen, Freda E.
    El-Deeb, Ibrahim Mustafa
    Zalucki, Yaramah
    Jennings, Michael P.
    Year published
    2021
    Metadata
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    Abstract
    BACKGROUND: Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat. OBJECTIVES: To evaluate whether PBT2/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides. METHODS: MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested ...
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    BACKGROUND: Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat. OBJECTIVES: To evaluate whether PBT2/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides. METHODS: MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested in combination with a sub-inhibitory concentration of PBT2/zinc. Serially diluted tetracycline was also tested with sub-inhibitory concentrations of PBT2/zinc and LL-37. SWATH-MS proteomic analysis of N. gonorrhoeae treated with PBT2/zinc, LL-37 and/or tetracycline was performed to determine the mechanism(s) of N. gonorrhoeae susceptibility to antibiotics and peptides. RESULTS: Sub-inhibitory concentrations of LL-37 and PBT2/zinc synergized to render strain WHO-Z susceptible to tetracycline, whereas the killing effect of PG-1 and PBT2/zinc was additive. SWATH-MS proteomic analysis suggested that PBT2/zinc most likely leads to a loss of membrane integrity and increased protein misfolding and, in turn, results in bacterial death. CONCLUSIONS: Here we show that PBT2, a candidate Alzheimer's and Huntington's disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic.
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    Journal Title
    Journal of Antimicrobial Chemotherapy
    DOI
    https://doi.org/10.1093/jac/dkab291
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Microbiology
    Medical microbiology
    Publication URI
    http://hdl.handle.net/10072/407634
    Collection
    • Journal articles

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