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In vitro activity and adaptation strategies of eravacycline in clinical Enterococcus faecium isolates from China

The Journal of Antibiotics volume 75, pages 498–508 (2022)Cite this article

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Abstract

Eravacycline (Erava) is a synthetic fluorocycline with potent antimicrobial activity against a wide range of Gram-positive bacteria. This study aimed to investigate the in vitro antimicrobial activity and resistance mechanism of Erava in clinical E. faecium isolates from China. Erava minimum inhibitory concentrations (MICs) against clinical E. faecium isolates—including those resistant to linezolid (LZD) or harboring the tetracycline (Tet) resistance genes was ≤0.25 mg l−1. Moreover, our data indicated that clinical isolates of E. faecium with Erava MIC 0.25 mg l−1 were predominantly shown to belong to Sequence-type 78 (ST78) and ST80. The prevalence of Erava heteroresistance in clinical E. faecium strain was 2.46% (3/122). The increased Erava MIC values of heteroresistance-derived E. faecium clones could be significantly reduced by efflux pump inhibitors (EPIs). Furthermore, comparative proteomics results showed that efflux pumps lmrA, mdlA, and mdlB contributed significantly to the acquisition of Erava resistance in E. faecium. In addition, a genetic mutation in 16 S rRNA (G190A) were detected in resistant E. faecium isolates induced by Erava. In summary, Erava exhibits potent in vitro antimicrobial activity against E. faecium, but mutation of Tet target sites and elevated expression of efflux pumps under Erava selection results in Erava resistance.

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Funding

This work was supported by the following grants: National Natural Science Foundation of China (82172283); Natural Science Foundation of Guangdong Province, China (2020A1515011049, 2020A1515111146, 2021A1515011727); Sanming Project of Medicine in Shenzhen (SMGC201705029); Shenzhen Key Medical Discipline Construction Fund (SZXK06162); Science, Technology and Innovation Commission of Shenzhen Municipality of basic research funds (JCYJ20180302144721183, JCYJ20180302144345028, JCYJ20190809110622729, JCYJ20190809110209389, JCYJ20190809102219774, JCYJ20190809151817062) and the Shenzhen Nanshan District Scientific Research Program of the People’s Republic of China (NS009, NS117, NS140, NS144, NS066, 2020012, 2020018, 2020040, 20200598).

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Author notes

  1. These authors contributed equally: Zewen Wen, Fangfang Liu, Peixing Zhang, Ying Wei

Authors and Affiliations

  1. Department of Infectious Diseases and Shenzhen Key Lab of Endogenous Infection, Shenzhen Nanshan People’s Hospital and the 6th affiliated hospital of Guangdong Medical University, Shenzhen, 518052, China

    Zewen Wen, Fangfang Liu, Peixing Zhang, Yiyi Shi, Jinxin Zheng, Zhijian Yu, Zhicao Xu, Qiwen Deng & Zhong Chen

  2. Quality Control Center of Hospital Infection Management of Shenzhen, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China

    Zewen Wen, Fangfang Liu, Peixing Zhang, Yiyi Shi, Jinxin Zheng, Guiqiu Li, Zhijian Yu, Zhicao Xu, Qiwen Deng & Zhong Chen

  3. Heilongjiang Medical Service Management Evaluation Center, Harbin, Heilongjiang, 150031, China

    Ying Wei

  4. The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China

    Guiqiu Li

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Contributions

ZC, QD and ZX participated in the design of the study and revised the manuscript carefully; ZW, FL, PZ and YW collected and identified strains, carried out the antibiotic susceptibility test, efflux inhibition assays and analyzed the data; YS, JZ and GL conducted the induction of Erava-resistance test and proteomics; ZY performed the CCs clustering analysis; ZC, QD, ZX and ZW wrote the manuscript incorporating comments from all authors. All the authors have read and agreed upon the submission.

Corresponding authors

Correspondence to Zhicao Xu, Qiwen Deng or Zhong Chen.

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This study was approved by the Ethics Committee of Shenzhen Nanshan people’s Hospital, the 6th Affiliated Hospital of Shenzhen University Health Science Center. For this type of study, formal consent is not required.

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Wen, Z., Liu, F., Zhang, P. et al. In vitro activity and adaptation strategies of eravacycline in clinical Enterococcus faecium isolates from China. J Antibiot 75, 498–508 (2022). https://doi.org/10.1038/s41429-022-00546-2

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