Overcoming tet(X)-harboring tigecycline resistance: a study on the efficacy of tigecycline-apramycin combinations

Juan Liu; Si-Lin Zheng; Jing-Jing Wu; Mei Zheng; Da-Tong Cai; Yan Zhang; Jian Sun; Xiao-Ping Liao; Yang Yu

doi:10.3389/fmicb.2024.1502558

Overcoming tet(X)-harboring tigecycline resistance: a study on the efficacy of tigecycline-apramycin combinations

Front Microbiol. 2024 Dec 23:15:1502558. doi: 10.3389/fmicb.2024.1502558. eCollection 2024.

Authors

Juan Liu^{1

2

3}, Si-Lin Zheng^{1

2}, Jing-Jing Wu^{1

2}, Mei Zheng^{1

2

4}, Da-Tong Cai^{1

2}, Yan Zhang^{1

2}, Jian Sun^{1

2

5}, Xiao-Ping Liao^{1

2

5}, Yang Yu^{1

2

5}

Affiliations

¹ Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
² State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
³ Guangdong Wenshi Dahuanong Biotechnology Co. Ltd., Yunfu, Guangdong, China.
⁴ Animal Laboratory Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
⁵ Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.

Abstract

Introduction: The emergence of the wide variety of novel tigecycline resistance tet(X) variants, including tet(X3), tet(X4), tet(X5), and tet(X6), has raised a serious threat to global public health and posed a significant challenge to the clinical treatment of multidrug-resistant bacterial infections.

Methods: In this study, we evaluated the synergism of tigecycline combining with other antibiotics as a means of overcoming the tet(X)-mediated resistance in Acinetobacter spp. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments, time-kill assays and dose-response curves. The in vivo synergistic effect of the combination was confirmed in a mouse model of thigh with neutrophilic granulocyte reduction. Additionally, combinations were tested for their ability to prevent high-level tigecycline-resistant mutants.

Results: We found that the combinations of tigecycline with apramycin exhibited synergistic activity against tet(X)-harboring Acinetobacter spp. with FICI of 0.088. The MICTGC decreased more than 5 times in the presence of subinhibitory levels of apramycin. The combination showed in vitro synergism in time-kill assays and in vivo therapeutic effectiveness in the mouse thigh infection model.

Discussion: This study shed light on the synergism of tigecycline in combination with apramycin which offers a viable therapeutic alternative for infections caused by tet(X)-harboring Acinetobacter spp.

Keywords: apramycin; mouse thigh infection model; synergistic combination therapy; tet(X)-harboring Acinetobacter spp.; tigecycline.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was jointly supported by the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (32121004); National key research and development program of China (2023YFD1800100); the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2019BT02N054); the National Key Research & Development Program of China (grant no. 2022YFE0103200); the Natural Science Foundation of Guangdong Province, China (General Program: 2022A1515011194); Double first-class discipline promotion project (2023B10564003); the 111 Center (D20008); the National Natural Science Foundation of China (grant no. 32002337) and the Guangdong provincial key research and development program (2023B0202150001).