AdeABC Efflux Pump Controlled by AdeRS Two Component System Conferring Resistance to Tigecycline, Omadacycline and Eravacycline in Clinical Carbapenem Resistant Acinetobacter nosocomialis.

Yi-Tzu Lee,Ya-Sung Yang,Yu-Ching Chou,Wei-Jane Hsu,Hsing-Yu Chen,I-Chieh Lin,Tein-Yao Chang,Jun-Ren Sun

doi:10.3389/fmicb.2020.584789

Abstract

Carbapenem-resistant Acinetobacter nosocomialis (CRAn) is a significant public health concern. Tigecycline non-susceptible CRAn (Tn-CRAn) isolates have emerged worldwide. Tigecycline resistance is mainly related to the overexpression of AdeABC efflux pump controlled by AdeRS two-component system (TCS). Two novel tetracycline derivatives, omadacycline and eravacycline, may present a treatment option for CRAn. This study investigated the in vitro antimicrobial activity of tigecycline, omadacycline and eravacycline against clinical CRAn isolates and the contribution of efflux pumps in their resistance. Eighty-nine clinical CRAn isolates, including 57 Tn-CRAn isolates were evaluated for minimum inhibitory concentrations (MICs) by the broth microdilution. The relationship between the antimicrobial resistance and efflux pump expression was assessed by their responses to the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). The contribution of the AdeABC efflux pump in their resistance was determined by the complementation of the AdeRS two-component system in wild-type, adeRS operon and adeB gene knockout strains. Among the 89 isolates, omadacycline and eravacycline MICs were correlated closely with those of tigecycline. They demonstrated improved potency, based on MIC90 values, by showing a 4 to 8-fold greater potency than tigecycline. The synergetic effects of tigecycline, omadacycline and eravacycline with NMP were observed in 57 (100%), 13 (22.8%), and 51 (89.5%) of Tn-CRAn isolates, respectively. Further analysis showed that the laboratory strain carrying the Type 1 adeRS operon increased the tigecycline, omadacycline and eravacycline MICs by 4–8-folds, respectively. Eravacycline demonstrated improved potency over tigecycline against populations of CRAn, including Tn-CRAn isolates. The over-expression of AdeABC efflux pumps was directly activated by the AdeRS two-component system and simultaneously reduced the susceptibilities of tigecycline, eravacycline, and omadacycline. Omadacycline and eravacycline MICs were correlated closely with those of eravacycline.

Highlights

Acinetobacter species has become a major nosocomial pathogen associated with high mortality in immunocompromised patients on account of its rapid acquisition of resistance (Ayoub Moubareck and Hammoudi Halat, 2020)
Between 2012 and 2018, clinical carbapenem resistant A. nosocomialis (CRAn) isolates were collected from AntimiCrobial studies in Taiwan Operating Network (ACTION), which included six medical centers located in different parts of Taiwan, including the Changhua Christian Hospital (CCH) in Central Taiwan, Kaohsiung Medical University Hospital (KMUH) in southern Taiwan, Mackay Memorial Hospital (MMH) in Northern Taiwan, National Taiwan University Hospital (NTUH) in Northern Taiwan, Taipei Veterans General Hospital (TVGH) in Northern Taiwan, Tri-Service General Hospital (TSGH) of the National Defense Medical Center (NDMC) in Northern Taiwan and National Institute of Infectious Diseases and Vaccinology, National Health Research Institute (NHRI) in Northern Taiwan
The Minimum inhibitory concentrations (MICs) of the three antibiotics did not increase while being transformed with those recombinant plasmids into the ATCC17903 adeB (An adeB) strain. These findings suggested that AdeABC efflux pumps medicated by AdeRS two-component system (TCS) played a role in the resistance to the three antibiotics in A. nosocomialis

Summary

Introduction

Acinetobacter species has become a major nosocomial pathogen associated with high mortality in immunocompromised patients on account of its rapid acquisition of resistance (Ayoub Moubareck and Hammoudi Halat, 2020). When Acinetobacter spp. develops extended drug resistance to sulbactam, tigecycline, and colistin, the antimicrobial choices become scarce and difficult (Montana et al, 2015). Acinetobacter nosocomialis is an emerging opportunistic pathogen that is usually grouped into the Acinetobacter calcoaceticus-baumannii complex (Acb complex) (Vijayakumar et al, 2019). In Asia, the carbapenem resistant rate among infections caused by A. nosocomialis is as high as 30% (Chen et al, 2018; Singkham-In and Chatsuwan, 2018; Chen et al, 2019). Tigecycline has been regarded as one of the final armamentaria against carbapenem resistant A. nosocomialis (CRAn). Tigecycline non-susceptible A. nosocomialis has increasingly emerged in recent years (Yang et al, 2019)

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