Zeng Weiliang, Feng Luozhu, Qian Changrui, Chen Tao, Wang Sipei, Zhang Ying, Zheng Xiangkuo, Wang Lingbo, Liu Shixing, Zhou Tieli, Sun Yao
Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
Front Microbiol. 2022 Apr 12;13:815600. doi: 10.3389/fmicb.2022.815600. eCollection 2022.
Daptomycin is a last-line antibiotic used in the treatment of multidrug-resistant infections. Alarmingly, daptomycin-resistant isolates have emerged. In this study, we investigated the evolution and mechanisms of daptomycin resistance in clinical isolates and the corresponding acquisition of collateral sensitivity (CS) as an evolutionary trade-off. We evolved daptomycin resistance in six daptomycin-susceptible isolates to obtain daptomycin-resistant mutants. The six strains successfully acquired high-level resistance to daptomycin , but this led to fitness costs in terms of growth, competition, and virulence. Mutations in , , and ; increased surface positive charge; thicker cell walls; and elevated expression of and were observed in daptomycin-resistant mutants. Surprisingly, we observed the emergence of CS in SC1762 isolates after the induction of daptomycin resistance. Compared with parental strains, the SC1174-D strain (i.e., daptomycin-resistant mutant of SC1174; non-CS) showed significantly upregulated expression of the gene cluster. However, in SC1762-D (i.e., daptomycin-resistant mutant of SC1762), all cluster genes except the gene were obviously downregulated. Further analyses revealed that an ISbased composite transposon was generated in SC1762-D, and it disrupted the gene, likely affecting the structure and expression of the gene cluster and resulting in resensitization to glycopeptides. Overall, this study reports a novel form of CS between daptomycin and glycopeptides in . Further, it provides a valuable foundation for developing effective regimens and sequential combinations of daptomycin and glycopeptides against .
达托霉素是一种用于治疗多重耐药感染的一线抗生素。令人担忧的是，已出现对达托霉素耐药的分离株。在本研究中，我们调查了临床分离株中达托霉素耐药性的演变和机制，以及作为进化权衡的相应附带敏感性（CS）的获得情况。我们在6株对达托霉素敏感的分离株中诱导出达托霉素耐药性，以获得达托霉素耐药突变体。这6株菌株成功获得了对达托霉素的高水平耐药性，但这在生长、竞争和毒力方面导致了适应性代价。在达托霉素耐药突变体中观察到 、 和 中的突变；表面正电荷增加；细胞壁增厚；以及 和 的表达升高。令人惊讶的是，在诱导达托霉素耐药性后，我们在SC1762分离株中观察到了CS的出现。与亲本菌株相比，SC1174-D菌株（即SC1174的达托霉素耐药突变体；非CS）显示 基因簇的表达显著上调。然而，在SC1762-D（即SC1762的达托霉素耐药突变体）中，除 基因外，所有 簇基因均明显下调。进一步分析表明，SC1762-D中产生了一个基于插入序列的复合转座子，它破坏了 基因，可能影响 基因簇的结构和表达，从而导致对糖肽类药物重新敏感。总体而言，本研究报道了 中达托霉素和糖肽类药物之间一种新的CS形式。此外，它为开发针对 的达托霉素和糖肽类药物的有效方案和序贯组合提供了有价值的基础。
