Identification of Privileged Antichlamydial Natural Products by a Ligand-Based Strategy

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 (IC value 0.3 μM). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.

Briaviolides K–N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum

“…ChemGPS-NP, a PCA (Principle Component Analysis)-based model applied to natural products, was first developed by the Backlund group in 2007 [ 11 ], and an entire online analysis system that provides the eight principal components (PCs) was further established by the same group in 2009 [ 12 ]. In the last few years, this computational tool has been employed to analyze structure-activity relationships (SAR) [ 13 , 14 ] and to further investigate promising pharmacological targets, guiding natural product drug discovery [ 15 , 16 , 17 ].…”

In vitro inhibitory effect of Hydrocotyle bonariensis Lam. extracts over Chlamydia trachomatis and Chlamydia pneumoniae on different stages of the chlamydial life cycle

“…Also, macrolides' massive use has raised resistance markers among other bacterial species (Bojang et al, 2017;Mohammadzadeh et al, 2019). All this evidence supports the need for constant efforts to continue searching for new antichlamydial agents (Alvesalo et al, 2006;Salin et al, 2010;Yamazaki et al, 2005;Osaka et al, 2012;Kahru et al, 2017;Petyaev et al, 2017).…”

Inhibitory Activity of Pyrroloisoxazolidine Derivatives against Chlamydia trachomatis

“…Until now, there is no effective vaccine for human use. These facts necessitate the continuous efforts to discover and develop novel nonantibiotic antichlamydial agents [16][17][18][19][20][21][22][23][24][25]. In search for antichlamydial agents from the synthesized compounds, we firstly reported that a group of pyrroloisoxazolidines inhibited C. trachomatis propagation.…”

“…However, no effective vaccine is available to prevent C. trachomatis infections up to date [13][14][15]. All these negative situations raise the pressing need to search for novel antichlamydial agents from natural materials or synthesized chemicals [16][17][18][19][20][21][22][23][24][25]. Isoxazolidine derivatives are a group of chemicals that possess a variety of biological and pharmaceutical activities including neuroactive, antioxidant, antibacterial, antifungal, and antiretroviral properties [26][27][28][29][30].…”