Recent advances in technologies for developing drugs against<i>Chlamydia pneumoniae</i>

Hanski, Leena; Vuorela, Pia

doi:10.1517/17460441.2014.915309

Cited by 9 publications

(13 citation statements)

References 89 publications

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“…Owing to its propensity for persistence, C. pneumoniae is a challenging target for antibacterial therapy. The bacterium can be eradicated from permissive cell lines such as the airway epithelium by macrolide and tetracycline antibiotics [14] but its complete eradication remains challenging. New strategies for combatting the persistent chlamydial populations are thus needed.…”

Section: Introductionmentioning

confidence: 99%

Assaying Chlamydia pneumoniae Persistence in Monocyte-Derived Macrophages Identifies Dibenzocyclooctadiene Lignans as Phenotypic Switchers

et al. 2020

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Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia–host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.

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Section: Introductionmentioning

confidence: 99%

Assaying Chlamydia pneumoniae Persistence in Monocyte-Derived Macrophages Identifies Dibenzocyclooctadiene Lignans as Phenotypic Switchers

et al. 2020

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“…C . pneumoniae is resistant to sulfa drugs and trimethoprim, and treatment with penicillins can trigger the formation of a persistent state [ 5 ]. Treatment of C .…”

Section: Introductionmentioning

confidence: 99%

“…Up to 30% of patients with C . pneumoniae -caused community acquired pneumonia harbor the bacterium in a cultivable form even after the treatment and symptoms have ceased [ 5 , 6 ]. Upon treatment failures and non-treated infections, the bacterium may convert to a chronic form characterized by morphological, transcriptional and metabolic changes different from the acute infectious phase.…”

Section: Introductionmentioning

confidence: 99%

Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae

et al. 2016

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We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen.

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“…In our previous review article, we have discussed the nonconventional antichlamydial agents identified within past ten years and highlighted the need for more narrow-spectrum or even chlamydia-specific antibacterial agents [7]. In the current contribution, we focus on describing the different approaches for antichlamydial drug discovery, with illustrative examples of successful use of each of them.…”

Section: Introductionmentioning

confidence: 99%

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

Hanski

Vuorela

2016

Microorganisms

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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.

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Recent advances in technologies for developing drugs againstChlamydia pneumoniae

Cited by 9 publications

References 89 publications

Assaying Chlamydia pneumoniae Persistence in Monocyte-Derived Macrophages Identifies Dibenzocyclooctadiene Lignans as Phenotypic Switchers

Assaying Chlamydia pneumoniae Persistence in Monocyte-Derived Macrophages Identifies Dibenzocyclooctadiene Lignans as Phenotypic Switchers

Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

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