Impact of azithromycin, doxycycline and redox-active small molecules on amoxicillin-induced Chlamydia pneumoniae persistence

Eveliina Taavitsainen-Wahlroos; Inés Reigada; Ilaria Sulmona; Leena Hanski

doi:10.1016/j.biopha.2023.115451

Impact of azithromycin, doxycycline and redox-active small molecules on amoxicillin-induced Chlamydia pneumoniae persistence

Biomed Pharmacother. 2023 Nov:167:115451. doi: 10.1016/j.biopha.2023.115451. Epub 2023 Sep 8.

Authors

Eveliina Taavitsainen-Wahlroos¹, Inés Reigada¹, Ilaria Sulmona², Leena Hanski³

Affiliations

¹ Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland.
² Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via Tommaso De Amicis 95, 80131, Naples, Italy.
³ Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. Electronic address: leena.hanski@helsinki.fi.

PMID: 37690390
DOI: 10.1016/j.biopha.2023.115451

Abstract

Amoxicillin is recommended as primary treatment for community-acquired bacterial pneumonia (CABP). 5-10% of CABP cases are caused by Chlamydia pneumoniae, an obligate intracellular bacterium which responds to beta-lactam antibiotics by converting to a persistent phenotype. To support rational pharmacotherapy of C. pneumoniae infections, we investigated how clinically relevant concentrations of azithromycin and doxycycline affect amoxicillin induced C. pneumoniae persistence. Given the known role of redox state alterations in the action of bactericidal antibiotics and widespread use of redox-active dietary supplements when experiencing respiratory symptoms, we also studied how redox active compounds affect the studied antibiotic treatments. Our data demonstrate that clinically applied amoxicillin concentrations (10 and 25 mg/l) fail to eradicate C. pneumoniae infection in respiratory epithelial cells. Transmission electron microscopy (TEM) of amoxicillin-treated C. pneumoniae infected cells reveal aberrant bacterial morphology characteristic of chlamydial stress response. Amoxicillin was also found to significantly limit the antichlamydial effect of azithromycin or doxycycline. However, based on quantitative culture and quantitative PCR data, azithromycin was superior to doxycycline in C. pneumoniae eradication either as monotherapy or in combination with amoxicillin. Amoxicillin was also found to decrease respiratory epithelial cell glutathione (GSH) levels, whereas redox-active dibenzocyclooctadiene lignans increased C. pneumoniae load in amoxicillin-treated cultures up to two-fold. These data highlight the impact of relative administration time on the efficacy of antichlamydial antibiotics and indicate unfavorable interactions between amoxicillin and redox-active small molecules.

Keywords: Aberrant body; Antibiotic combination; Bacterial persistence; Beta-lactam; Glutathione; Redox-active small molecules.