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bioRxiv · 10.64898/2026.03.19.712910

Coordinated topoisomerase function shapes the fluoroquinolone response of Chlamydia trachomatis

Shen, L.·Terrebonne, A.·Diggs, C.·Ouellette, S. P.·Tse-Dinh, Y.-C.·Gao, L.
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Abstract

DNA supercoiling is essential for the developmental cycle of Chlamydia trachomatis, yet its role in shaping antibiotic responses remains poorly understood. We investigated how the fluoroquinolone moxifloxacin (Mox) influenced C. trachomatis growth across developmental stages with its distinct supercoiling levels. Early Mox exposure completely halted bacterial growth, whereas treatment during mid-cycle produced enlarged, persistent forms and abolished formation of infectious progeny. These stage-specific outcomes coincided with inhibition of DNA replication, depletion of DNA gyrase, and transcriptional repression of ompA and omcB, accompanied by preserved or elevated expression of the stress-responsive groESL1 operon. Mox also elicited compensatory downregulation of topoisomerase I (TopA), consistent with attempts to rebalance intracellular supercoiling. Together, these data demonstrate that fluoroquinolone susceptibility in C. trachomatis reflects stage-dependent supercoiling levels. Perturbation of supercoiling homeostasis drives developmental arrest and persistence phenotypes, highlighting coordinated gyrase-TopA activity as a key determinant of fluoroquinolone tolerance and a potential target for overcoming persistent infection. ImportanceC. trachomatis, a medically significant bacterial pathogen, can persist under antimicrobial pressure, complicating treatment strategy. This study links supercoiling homeostasis to fluoroquinolone tolerance, offering mechanistic insights into chlamydial adaptation to antibiotic stress and identifying potential targets to overcome persistence--an urgent challenge in global reproductive health.

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Shen, L., Terrebonne, A., Diggs, C., Ouellette, S. P., Tse-Dinh, Y.-C., Gao, L.. 2026-03-19. Coordinated topoisomerase function shapes the fluoroquinolone response of Chlamydia trachomatis. https://doi.org/10.64898/2026.03.19.712910

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