Abstract
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.
Highlights
In the course of evolution, bacteria have developed various means for protecting themselves from unfavorable conditions
We have identified the antichlamydial activity of dibenzocyclooctadiene lignans isolated from a medicinal plant Schisandra chinensis on C. pneumoniae replication in respiratory epithelial cells [15,16]
As the dibenzocyclooctadiene are known for theirwe redox activities and changes ineffects cellular redox status have been linkedlignans to bacterial persistence, addressed the differential of redox status have been linked to bacterial persistence, we addressed the differential effects of schisandrin and schisandrin C on C. pneumoniae infection by studying changes in cellular redox status
Summary
In the course of evolution, bacteria have developed various means for protecting themselves from unfavorable conditions. Described as a reversible dormant phenotype, persistence has been acknowledged as one major survival strategy of bacteria [1,2,3]. Molecules 2020, 25, 294 to survive under antibiotic pressure and revert back to metabolically more active phenotype when stressful conditions are cleared off. Bacterial dormancy is associated with hard-to-treat infections via two mechanistically overlapping phenomena; persistent infections evading host immune responses and antibiotic persistence defined based on the presence of drug-tolerant subpopulations of bacteria. Both of these features are typical to infections caused by Chlamydia pneumoniae, a gram-negative obligate intracellular human pathogen that causes respiratory infections from dry cough to pneumonia
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