Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time.
Martijn Zwama,Kunihiko Nishino +1 more
TLDR
In this article, the authors take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella-enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila).Abstract:
The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.read more
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Molecular mechanisms of antibiotic resistance revisited
Elizabeth M Darby,Eleftheria Trampari,Pauline Siasat,Maria Solsona Gaya,Ilyas Alav,Marc Weber,Jessica M A Blair +6 more
TL;DR: In this paper , the authors explore recent advances in understanding how resistance genes contribute to the biology of the host, new structural details of relevant molecular events underpinning resistance, the identification of new resistance gene families and the interactions between different resistance mechanisms.
Journal ArticleDOI
Bacterial Multidrug Efflux Pumps at the Frontline of Antimicrobial Resistance: An Overview
Lulu Huang,Cuirong Wu,Haijiao Gao,C. Z. Xu,Menghong Dai,Lingli Huang,Haihong Hao,Xu Wang,Guyue Cheng +8 more
TL;DR: The biological functions of efflux pump-related genes/proteins including their promotion of multidrug resistance, biofilm formation, quorum sensing, and survival and pathogenicity of bacteria are elucidated and the potential applications are analyzed.
Journal ArticleDOI
Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms.
Alina Ornik-Cha,Julia Wilhelm,Jessica Kobylka,Hanno Sjuts,Attilio Vittorio Vargiu,Giuliano Malloci,Julian Reitz,Anja Seybert,Achilleas S. Frangakis,Klaas M. Pos +9 more
TL;DR: In this paper, the authors show the 3.5-dimensional structure of subunit AdeB from the Acinetobacter baumannii AdeABC efflux pump solved by single-particle cryo-electron microscopy.
Journal ArticleDOI
Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria
Nina Compagne,Anais Vieira Da Cruz,Reinke T. Müller,Ruben C. Hartkoorn,Marion Flipo,Klaas M. Pos +5 more
TL;DR: In this paper , the authors present eight families of efflux pump inhibitors (EPIs) active against Escherichia coli or Pseudomonas aeruginosa, and their binding sites and their mechanisms of action are analyzed comparatively.
Journal ArticleDOI
What Approaches to Thwart Bacterial Efflux Pumps-Mediated Resistance?
TL;DR: Questions about the role of EPs in the establishment of multidrug resistance, and what weapons do the authors have to thwart EP-mediated resistance, are addressed in the present review.
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