Xu Congjuan, Feng Jie, Zhou Yuchen, Ren Huan, Pan Xiaolei, Chen Shuiping, Liu Xuehua, Li Guanxian, Li Jinjin, Geng Bin, Gao Linlin, Cheng Zhihui, Jin Yongxin, Ha Un-Hwan, Jin Shouguang, Lamont Iain L, Pletzer Daniel, Wu Weihui
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China.
Department of Infection and Control, 5th Medical Center of PLA General Hospital, Beijing, China.
J Bacteriol. 2025 May 22;207(5):e0055224. doi: 10.1128/jb.00552-24. Epub 2025 Apr 30.
Antibiotic combinations can slow down resistance development and/or achieve synergistic therapeutic effects. In this study, we observed that a combined use of ceftazidime-avibactam (CZA) with azithromycin effectively repressed CZA resistance development in . Transcriptome analysis revealed that subinhibitory concentrations of azithromycin reduced the expression of genes involved in stress-induced mutagenesis, including the stress response sigma factor . Interestingly, ribosome profiling revealed global redistribution of ribosomes by azithromycin, among which ribosome stalling was significantly intensified near the 5´ terminus of the mRNA. Further DNA mutational analysis revealed that azithromycin represses the translation of through its 5´-terminal rare codons, which in turn reduced its transcription. These observations have been recapitulated where azithromycin-repressed CZA resistance development when was passaged in mice. Overall, our study revealed the molecular mechanism of azithromycin-mediated repression of antibiotic resistance development, providing a promising antibiotic combination for the treatment of infections.IMPORTANCEAntibiotic resistance, a global public health challenge, demands the development of novel antibiotics and therapeutic strategies. Ceftazidime-avibactam (CZA) is a combination of a β-lactam antibiotic with a β-lactamase inhibitor that is effective against various gram-negative bacteria such as . However, clinical CZA-resistant isolates have been reported. Here, we found that combining CZA with azithromycin can effectively suppress the development of resistance in and . Moreover, we found that azithromycin represses the translation initiation of through its 5´-terminal rare and less frequent codons, thereby subsequently reducing the mutational frequency of CZA resistance. Therefore, our work provides a promising antibiotic combination for the treatment of infections.
抗生素联合使用可以减缓耐药性的产生和/或实现协同治疗效果。在本研究中，我们观察到头孢他啶-阿维巴坦（CZA）与阿奇霉素联合使用可有效抑制[具体细菌名称未给出]中CZA耐药性的产生。转录组分析表明，亚抑菌浓度的阿奇霉素可降低参与应激诱导突变的基因表达，包括应激反应西格玛因子[具体因子名称未给出]。有趣的是，核糖体分析显示阿奇霉素可使核糖体发生全局重新分布，其中在[具体mRNA名称未给出]的mRNA 5´末端附近核糖体停滞显著加剧。进一步的DNA突变分析表明，阿奇霉素通过其5´末端的稀有密码子抑制[具体基因名称未给出]的翻译，进而降低其转录水平。当[具体细菌名称未给出]在小鼠体内传代时，阿奇霉素抑制CZA耐药性产生的这些观察结果得到了重现。总体而言，我们的研究揭示了阿奇霉素介导的抗生素耐药性产生抑制的分子机制，为治疗[具体感染类型未给出]感染提供了一种有前景的抗生素联合方案。重要性抗生素耐药性是一项全球公共卫生挑战，需要开发新型抗生素和治疗策略。头孢他啶-阿维巴坦（CZA）是一种β-内酰胺抗生素与β-内酰胺酶抑制剂的组合，对多种革兰氏阴性菌如[具体细菌名称未给出]有效。然而，已有临床CZA耐药菌株的报道。在这里，我们发现将CZA与阿奇霉素联合使用可有效抑制[具体细菌名称未给出]和[具体细菌名称未给出]中耐药性的产生。此外，我们发现阿奇霉素通过其5´末端的稀有和低频密码子抑制[具体基因名称未给出]的翻译起始，从而随后降低CZA耐药性的突变频率。因此，我们的工作为治疗[具体感染类型未给出]感染提供了一种有前景的抗生素联合方案。
