ORIGINAL RESEARCH article
Front. Med.
Sec. Infectious Diseases: Pathogenesis and Therapy
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1552537
Copper enhances tetracycline resistance via the efflux transporter CrdAB-CzcBA in Helicobacter pylori
Provisionally accepted
- Fujian Medical University, Fuzhou, China
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Helicobacter pylori infection is a significant risk factor for various gastrointestinal diseases, while the standard triple therapy for its eradication is increasingly compromised by antibiotic resistance. This study investigates the role of the CrdAB-CzcBA efflux pump and its regulation by copper in tetracycline resistance in H. pylori. Using minimum inhibitory concentration (MIC) determination and growth curve analysis, we found that the deletion of crdA or czcA significantly reduced tetracycline resistance, while overexpression of CrdAB-CzcBA under the urease promoter enhanced bacterial resistance by reducing intracellular tetracycline accumulation. Ethidium bromide and tetracycline accumulation assays confirmed that CrdAB-CzcBA mediates active efflux of tetracycline, contributing to reduced intracellular drug levels. Furthermore, copper supplementation upregulated the expression of CrdAB-CzcBA via the CrdRS two-component system, thereby promoting bacterial growth under tetracycline stress. Notably, copper-induced resistance was abrogated in ΔcrdR mutants, demonstrating the dependence of this mechanism on CrdRS. These findings highlight CrdAB-CzcBA as a critical efflux system in tetracycline resistance and emphasize the role of environmental factors, such as copper, in modulating bacterial antibiotic resistance, underscoring the need for strategies that account for metal ion influences in managing H. pylori infections.
Keywords: H. pylori, Copper, Efflux transporter, CrdAB-CzcBA, Tetracycline Resistance
Received: 28 Dec 2024; Accepted: 08 Jul 2025.
Copyright: © 2025 Gao, Xiang, Zhang, Huang, She and Wen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Feifei She, Fujian Medical University, Fuzhou, China
Yancheng Wen, Fujian Medical University, Fuzhou, China
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