Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

Abstract

Throughout its known history, the gram-negative bacterium Chlamydia pneumoniae has remained a challenging target for antibacterial chemotherapy and drug discovery. Owing to its well-known propensity for persistence and recent reports on antimicrobial resistence within closely related species, new approaches for targeting this ubiquitous human pathogen are urgently needed. In this review, we describe the strategies that have been successfully applied for the identification of nonconventional antichlamydial agents, including target-based and ligand-based virtual screening, ethnopharmacological approach and pharmacophore-based design of antimicrobial peptide-mimicking compounds. Among the antichlamydial agents identified via these strategies, most translational work has been carried out with plant phenolics. Thus, currently available data on their properties as antichlamydial agents are described, highlighting their potential mechanisms of action. In this context, the role of mitogen-activated protein kinase activation in the intracellular growth and survival of C. pneumoniae is discussed. Owing to the complex and often complementary pathways applied by C. pneumoniae in the different stages of its life cycle, multitargeted therapy approaches are expected to provide better tools for antichlamydial therapy than agents with a single molecular target.

Keywords: Chlamydia pneumoniae; antichlamydial agent; antimicrobial peptide; plant phenolics.

Figure 1

The lead optimization gives information via structure–activity relationships that will be basis to synthesize the next generation of lead compounds.

Figure 2

Impact of known MAP kinase inhibitors and luteolin on C. pneumoniae inclusion counts in human epithelial cells (HL). HL cells (400.000 cells/well) were inoculated with C. pneumoniae strain K7 (multiplicity of infection 0.2) and p38 (SB202190 and SB203580), ERK1/2 (UO126 and FR180204) and JNK (TCSJNK60 and SP60012) inhibitors were administered into the cultures 2 h post inoculation (p.i.), followed by immunofluorescent detection of chlamydial inclusions at 72 h p.i. All presented inhibition values are statistically significant compared to untreated control infections.