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 Universitygrid.216938.7, Tianjin, China.
Department of Laboratory Medicine, 5th Medical Center of PLA General Hospital, Beijing, China.
Microbiol Spectr. 2022 Oct 26;10(5):e0139022. doi: 10.1128/spectrum.01390-22. Epub 2022 Aug 16.
The evolution of bacterial antibiotic resistance is exhausting the list of currently used antibiotics and endangers those in the pipeline. The combination of antibiotics is a promising strategy that may suppress resistance development and/or achieve synergistic therapeutic effects. Eravacycline is a newly approved antibiotic that is effective against a variety of multidrug-resistant (MDR) pathogens. However, the evolution of resistance to eravacycline and strategies to suppress the evolution remain unexplored. Here, we demonstrated that a carbapenem-resistant Klebsiella pneumoniae clinical isolate quickly developed resistance to eravacycline, which is mainly caused by mutations in the gene encoding the Lon protease. The evolved resistant mutants display collateral sensitivities to β-lactam/β-lactamase inhibitor (BLBLI) combinations aztreonam/avibactam and ceftazidime-avibactam. Proteomic analysis revealed upregulation of the multidrug efflux system AcrA-AcrB-TolC and porin proteins OmpA and OmpU, which contributed to the increased resistance to eravacycline and susceptibility to BLBLIs, respectively. The combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam suppresses resistance development. We further demonstrated that eravacycline-resistant mutants evolved from an NDM-1-containing K. pneumoniae strain display collateral sensitivity to aztreonam/avibactam, and the combination of eravacycline with aztreonam/avibactam suppresses resistance development. In addition, the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam displayed synergistic therapeutic effects in a murine cutaneous abscess model. Overall, our results revealed mechanisms of resistance to eravacycline and collateral sensitivities to BLBLIs and provided promising antibiotic combinations in the treatment of multidrug-resistant K. pneumoniae infections. The increasing bacterial antibiotic resistance is a serious threat to global public health, which demands novel antimicrobial medicines and treatment strategies. Eravacycline is a newly approved antibiotic that belongs to the tetracycline antibiotics. Here, we found that a multidrug-resistant Klebsiella pneumoniae clinical isolate rapidly developed resistance to eravacycline and the evolved resistant mutants displayed collateral sensitivity to antibiotics aztreonam/avibactam and ceftazidime-avibactam. We demonstrated that the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam repressed resistance development and improved the treatment efficacies. We also elucidated the mechanisms that contribute to the increased resistance to eravacycline and susceptibility to aztreonam/avibactam and ceftazidime-avibactam. This work demonstrated the mechanisms of antibiotic resistance and collateral sensitivity and provided a new therapeutically option for effective antibiotic combinations.
细菌对抗生素的耐药性不断进化，使目前使用的抗生素种类逐渐枯竭，并危及正在研发中的抗生素。抗生素联合使用是一种很有前景的策略，可能会抑制耐药性的发展和/或实现协同治疗效果。依拉环素是一种新批准的抗生素，对多种多药耐药（MDR）病原体有效。然而，依拉环素耐药性的进化以及抑制耐药性进化的策略仍有待探索。在这里，我们证明了一种耐碳青霉烯类的肺炎克雷伯菌临床分离株很快对依拉环素产生了耐药性，这主要是由编码 Lon 蛋白酶的基因发生突变所致。进化而来的耐药突变体对β-内酰胺/β-内酰胺酶抑制剂（BLBLI）组合氨曲南/阿维巴坦和头孢他啶-阿维巴坦表现出交叉敏感性。蛋白质组学分析显示，多药外排系统 AcrA-AcrB-TolC 和孔蛋白 OmpA 和 OmpU 的表达上调，这分别导致了对依拉环素的耐药性增加和对 BLBLIs 的敏感性增加。依拉环素与氨曲南/阿维巴坦或头孢他啶-阿维巴坦联合使用可抑制耐药性的发展。我们进一步证明，来自携带 NDM-1 的肺炎克雷伯菌菌株的依拉环素耐药突变体对氨曲南/阿维巴坦表现出交叉敏感性，依拉环素与氨曲南/阿维巴坦联合使用可抑制耐药性的发展。此外，依拉环素与氨曲南/阿维巴坦或头孢他啶-阿维巴坦联合使用在小鼠皮肤脓肿模型中显示出协同治疗效果。总之，我们的研究结果揭示了依拉环素耐药的机制以及对 BLBLIs 的交叉敏感性，并为治疗多药耐药肺炎克雷伯菌感染提供了有前景的抗生素联合治疗方案。不断增加的细菌抗生素耐药性是对全球公共健康的严重威胁，这需要新型抗菌药物和治疗策略。依拉环素是一种新批准的抗生素，属于四环素类抗生素。在这里，我们发现一种多药耐药的肺炎克雷伯菌临床分离株对依拉环素迅速产生耐药性，而进化而来的耐药突变体对氨曲南/阿维巴坦和头孢他啶-阿维巴坦表现出交叉敏感性。我们证明了依拉环素与氨曲南/阿维巴坦或头孢他啶-阿维巴坦联合使用可以抑制耐药性的发展，并提高治疗效果。我们还阐明了导致对依拉环素耐药性增加和对氨曲南/阿维巴坦和头孢他啶-阿维巴坦敏感性增加的机制。这项工作揭示了抗生素耐药性和交叉敏感性的机制，并为有效的抗生素联合治疗提供了新的治疗选择。
