A1 Refereed original research article in a scientific journal
Identification of Privileged Antichlamydial Natural Products by a Ligand-Based Strategy
Authors: Elina Karhu, Janne Isojärvi, Pia Vuorela, Leena Hanski, Adyary Fallarero
Publisher: AMER CHEMICAL SOC
Publication year: 2017
Journal: Journal of Natural Products
Journal name in source: JOURNAL OF NATURAL PRODUCTS
Journal acronym: J NAT PROD
Volume: 80
Issue: 10
First page : 2602
Last page: 2608
Number of pages: 7
ISSN: 0163-3864
DOI: https://doi.org/10.1021/acs.jnatprod.6b01052(external)
Abstract
The obligate intracellular pathogen Chlamydia pneumoniae remains a difficult target for antimicrobial therapy. Owing to the permeability barrier placed by bacterial and host vacuolar membranes, as well as the propensity of the bacterium for persistent infections, treatment failures are common. Despite the urgent need for new antichlamydial compounds, their discovery is challenged by the technically demanding assay procedures and lack of validated targets. An alternative strategy of using naturally occurring compounds and their derivatives against C. pneumoniae is presented. The strategy consists of the application of ligand-based virtual screening to a natural product library of 502 compounds with the ChemGPS-NP chemography tool followed by in vitro antichlamydial assays. The reference set used for the 2D similarity search was constructed of 19 known antichlamydial compounds of plant origin. Based on the similarity screen, 53 virtual hits were selected for in vitro testing. Six compounds (leads) were identified that cause >= 50% C. pneumoniae growth inhibition and showed no impact on host cell viability. The leads fall into completely new antichlamydial chemotypes, one of them being mycophenolic acid (IC50 value 0.3 mu M). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.
The obligate intracellular pathogen Chlamydia pneumoniae remains a difficult target for antimicrobial therapy. Owing to the permeability barrier placed by bacterial and host vacuolar membranes, as well as the propensity of the bacterium for persistent infections, treatment failures are common. Despite the urgent need for new antichlamydial compounds, their discovery is challenged by the technically demanding assay procedures and lack of validated targets. An alternative strategy of using naturally occurring compounds and their derivatives against C. pneumoniae is presented. The strategy consists of the application of ligand-based virtual screening to a natural product library of 502 compounds with the ChemGPS-NP chemography tool followed by in vitro antichlamydial assays. The reference set used for the 2D similarity search was constructed of 19 known antichlamydial compounds of plant origin. Based on the similarity screen, 53 virtual hits were selected for in vitro testing. Six compounds (leads) were identified that cause >= 50% C. pneumoniae growth inhibition and showed no impact on host cell viability. The leads fall into completely new antichlamydial chemotypes, one of them being mycophenolic acid (IC50 value 0.3 mu M). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.
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