环丙沙星耐药猪链球菌通过增加抗生素胞内蓄积对加米霉素产生附属敏感性的机制

doi:10.1016/j.jia.2024.12.005

Journal of Integrative Agriculture ›› 2026, Vol. 25 ›› Issue (7): 2959-2969.DOI: 10.1016/j.jia.2024.12.005

环丙沙星耐药猪链球菌通过增加抗生素胞内蓄积对加米霉素产生附属敏感性的机制

收稿日期:2024-06-01 修回日期:2024-12-05 接受日期:2024-10-22 出版日期:2026-07-20 发布日期:2026-06-09

Collateral sensitivity to gamithromycin in ciprofloxacin-resistant Streptococcus suis is driven by increasing intracellular antibiotic accumulation

Yuejun Zhang^{1, 2}, Mengting Tao³, Ruiling Wang^{1, 2}, Zilin Shi^{1, 2}, Peipei Li^{1, 2}, Sijia Tang^{1, 2}, Jian Sun^{1, 2, 4}, Xiaoping Liao^{1, 2, 4}, Yufeng Zhou^{1, 2, 4#}

¹ State Key Laboratory of Animal Disease Control and Prevention, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
²Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, China
³Institute of Laboratory Animal Science, Jinan University, Guangzhou 510632, China
⁴Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou 225009, China

Received:2024-06-01 Revised:2024-12-05 Accepted:2024-10-22 Online:2026-07-20 Published:2026-06-09
About author:#Correspondence Yufeng Zhou, Tel/Fax: +86-20-85288387, E-mail: zyf@scau.edu.cn
Supported by:
This work was supported by the National Key Research and Development Program of China (2023YFD1800100), the National Natural Science Foundation of China (32172909 and 31902318), the Guangdong Basic and Applied Basic Research Foundation, China (2024A1515010365), the Foundation for Innovative Research Groups of National Natural Science Foundation of China (32121004), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program, China (2019BT02N054), the Double First-Class Discipline Promotion Project, China (2023B10564003) and the 111 Center, China (D20008).

摘要/Abstract

摘要：

作为一种重要的人畜共患病原菌，猪链球菌因其对抗生素的多重耐药性以及对猪群和人类健康构成的威胁而日益受到关注，迫切需要有效的治疗策略。附属敏感性（collateral sensitivity）是指细菌在对一种抗生素产生耐药性的同时，对另一种抗生素的敏感性增强的现象，这一机制为应对细菌耐药性的进化提供了新的思路。本研究通过实验室诱导成功获得了对11种临床常见抗生素耐药的猪链球菌亚群，并详细描绘了抗生素耐药猪链球菌的附属敏感性图谱及其复杂的敏感性关联特征。结果表明，对环丙沙星耐药的猪链球菌在体内外均表现出对加米霉素的显著附属敏感性。同时，加米霉素能有效限制猪链球菌对氟喹诺酮类药物耐药性的进化，并缩小其突变选择窗（mutant selection windows, MSW）的范围。进一步的机制研究揭示，在环丙沙星药物压力下，耐药猪链球菌由于钾离子转运蛋白基因（ktrB）和多药外排泵基因（pmrA）的突变，导致菌株膜电位的改变和质子动力势（proton-motive force, PMF）依赖的外排泵功能降低，这显著增加了抗生素在菌体的胞内积累，并最终导致了对加米霉素的附属敏感性。小鼠大腿感染的体内治疗结果进一步证实，基于附属敏感机制的加米霉素治疗方案对环丙沙星耐药猪链球菌感染具有更好的疗效、更低的药效学靶值和更高的治疗成功率。综上所述，本研究阐明了加米霉素对环丙沙星耐药猪链球菌产生附属敏感性的机制，为基于附属敏感机制设计耐药猪链球菌感染的治疗方案提供了新的思路。

Abstract:

Streptococcus suis has garnered increasing attention due to its implication in severe infections in both swine and humans, as well as its development of multidrug resistance. The phenomenon of collateral sensitivity, whereby resistance to one antibiotic leads to increased sensitivity to another, provides new opportunities for mitigating the evolution of resistance. In this study, we evolved resistance in S. suis to 11 clinically used antibiotics and characterized the resulting collateral sensitivity profiles, revealing a complex network of interactions. Based on our findings, we identified dozens of such drug pairs and demonstrated collateral sensitivity to gamithromycin in ciprofloxacin-resistant S. suis both in vitro and in vivo. Gamithromycin effectively limits the evolution of resistance and reduces the mutant selection window for ciprofloxacin-resistant S. suis strains. Mechanistic studies indicated that the heightened sensitivity of ciprofloxacin-resistant S. suis to gamithromycin was associated with increased intracellular gamithromycin accumulation due to membrane potential alterations and reduced functions of proton motive force (PMF)-dependent efflux pumps. Furthermore, collateral sensitivity-based treatments significantly resensitized ciprofloxacin-resistant S. suis strains to gamithromycin, resulting in superior efficacy, lower pharmacodynamic targets, and higher treatment success rates in a murine thigh infection model. Our results indicate that gamithromycin sensitivity in S. suis is a collateral consequence of resistance to ciprofloxacin, providing valuable insight for the strategic design of collateral sensitivity-based antibiotic therapies for S. suis infections.

Key words: collateral sensitivity , S. suis , gamithromycin , ciprofloxacin

Yuejun Zhang, Mengting Tao, Ruiling Wang, Zilin Shi, Peipei Li, Sijia Tang, Jian Sun, Xiaoping Liao, Yufeng Zhou. 环丙沙星耐药猪链球菌通过增加抗生素胞内蓄积对加米霉素产生附属敏感性的机制[J]. Journal of Integrative Agriculture, 2026, 25(7): 2959-2969.

Yuejun Zhang, Mengting Tao, Ruiling Wang, Zilin Shi, Peipei Li, Sijia Tang, Jian Sun, Xiaoping Liao, Yufeng Zhou. Collateral sensitivity to gamithromycin in ciprofloxacin-resistant Streptococcus suis is driven by increasing intracellular antibiotic accumulation[J]. Journal of Integrative Agriculture, 2026, 25(7): 2959-2969.

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环丙沙星耐药猪链球菌通过增加抗生素胞内蓄积对加米霉素产生附属敏感性的机制

Collateral sensitivity to gamithromycin in ciprofloxacin-resistant Streptococcus suis is driven by increasing intracellular antibiotic accumulation

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