Cargando…

A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae

The increasing incidence of tigecycline resistance undoubtedly constitutes a serious threat to global public health. The combination therapies had become the indispensable strategy against this threat. Herein, 11 clinical tigecycline-resistant Klebsiella pneumoniae which mainly has mutations in ramR...

Descripción completa

Detalles Bibliográficos
Autores principales: Sun, Lilan, Sun, Lang, Li, Xue, Hu, Xinxin, Wang, Xiukun, Nie, Tongying, Zhang, Youwen, You, Xuefu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766836/
https://www.ncbi.nlm.nih.gov/pubmed/35071055
http://dx.doi.org/10.3389/fcimb.2021.809542
_version_ 1784634613656715264
author Sun, Lilan
Sun, Lang
Li, Xue
Hu, Xinxin
Wang, Xiukun
Nie, Tongying
Zhang, Youwen
You, Xuefu
author_facet Sun, Lilan
Sun, Lang
Li, Xue
Hu, Xinxin
Wang, Xiukun
Nie, Tongying
Zhang, Youwen
You, Xuefu
author_sort Sun, Lilan
collection PubMed
description The increasing incidence of tigecycline resistance undoubtedly constitutes a serious threat to global public health. The combination therapies had become the indispensable strategy against this threat. Herein, 11 clinical tigecycline-resistant Klebsiella pneumoniae which mainly has mutations in ramR, acrR, or macB were collected for tigecycline adjuvant screening. Interestingly, ML-7 hydrochloride (ML-7) dramatically potentiated tigecycline activity. We further picked up five analogs of ML-7 and evaluated their synergistic activities with tigecycline by using checkerboard assay. The results revealed that ML-7 showed certain synergy with tigecycline, while other analogs exerted attenuated synergistic effects among tigecycline-resistant isolates. Thus, ML-7 was selected for further investigation. The results from growth curves showed that ML-7 combined with tigecycline could completely inhibit the growth of bacteria, and the time-kill analysis revealed that the combination exhibited synergistic bactericidal activities for tigecycline-resistant isolates during 24 h. The ethidium bromide (EtBr) efflux assay demonstrated that ML-7 could inhibit the functions of efflux pump. Besides, ML-7 disrupted the proton motive force (PMF) via increasing ΔpH, which in turn lead to the inhibition of the functions of efflux pump, reduction of intracellular ATP levels, as well as accumulation of ROS. All of which promoted the death of bacteria. And further transcriptomic analysis revealed that genes related to the mechanism of ML-7 mainly enriched in ABC transporters. Taken together, these results revealed the potential of ML-7 as a novel tigecycline adjuvant to circumvent tigecycline-resistant Klebsiella pneumoniae.
format Online
Article
Text
id pubmed-8766836
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-87668362022-01-20 A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae Sun, Lilan Sun, Lang Li, Xue Hu, Xinxin Wang, Xiukun Nie, Tongying Zhang, Youwen You, Xuefu Front Cell Infect Microbiol Cellular and Infection Microbiology The increasing incidence of tigecycline resistance undoubtedly constitutes a serious threat to global public health. The combination therapies had become the indispensable strategy against this threat. Herein, 11 clinical tigecycline-resistant Klebsiella pneumoniae which mainly has mutations in ramR, acrR, or macB were collected for tigecycline adjuvant screening. Interestingly, ML-7 hydrochloride (ML-7) dramatically potentiated tigecycline activity. We further picked up five analogs of ML-7 and evaluated their synergistic activities with tigecycline by using checkerboard assay. The results revealed that ML-7 showed certain synergy with tigecycline, while other analogs exerted attenuated synergistic effects among tigecycline-resistant isolates. Thus, ML-7 was selected for further investigation. The results from growth curves showed that ML-7 combined with tigecycline could completely inhibit the growth of bacteria, and the time-kill analysis revealed that the combination exhibited synergistic bactericidal activities for tigecycline-resistant isolates during 24 h. The ethidium bromide (EtBr) efflux assay demonstrated that ML-7 could inhibit the functions of efflux pump. Besides, ML-7 disrupted the proton motive force (PMF) via increasing ΔpH, which in turn lead to the inhibition of the functions of efflux pump, reduction of intracellular ATP levels, as well as accumulation of ROS. All of which promoted the death of bacteria. And further transcriptomic analysis revealed that genes related to the mechanism of ML-7 mainly enriched in ABC transporters. Taken together, these results revealed the potential of ML-7 as a novel tigecycline adjuvant to circumvent tigecycline-resistant Klebsiella pneumoniae. Frontiers Media S.A. 2022-01-05 /pmc/articles/PMC8766836/ /pubmed/35071055 http://dx.doi.org/10.3389/fcimb.2021.809542 Text en Copyright © 2022 Sun, Sun, Li, Hu, Wang, Nie, Zhang and You https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Sun, Lilan
Sun, Lang
Li, Xue
Hu, Xinxin
Wang, Xiukun
Nie, Tongying
Zhang, Youwen
You, Xuefu
A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae
title A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae
title_full A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae
title_fullStr A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae
title_full_unstemmed A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae
title_short A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae
title_sort novel tigecycline adjuvant ml-7 reverses the susceptibility of tigecycline-resistant klebsiella pneumoniae
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766836/
https://www.ncbi.nlm.nih.gov/pubmed/35071055
http://dx.doi.org/10.3389/fcimb.2021.809542
work_keys_str_mv AT sunlilan anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT sunlang anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT lixue anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT huxinxin anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT wangxiukun anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT nietongying anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT zhangyouwen anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT youxuefu anoveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT sunlilan noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT sunlang noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT lixue noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT huxinxin noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT wangxiukun noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT nietongying noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT zhangyouwen noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae
AT youxuefu noveltigecyclineadjuvantml7reversesthesusceptibilityoftigecyclineresistantklebsiellapneumoniae