Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

Langevin, Ariel M.; Meouche, Imane El; Dunlop, Mary J.

doi:10.1128/msphere.01056-20

Cited by 18 publications

(14 citation statements)

References 64 publications

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“…In both these studies, the direct effects of the mutations were not determined. 2020) examined the evolution of mutations in E. coli and AcrAB-TolC specifically, respectively, under chloramphenicol growth conditions, and both studies observed the V139F mutation in AcrB-Ec [114,115]. This mutation was also seen by Hoeksema et al (2019) when analyzing the effects of mutations in genes related to AMR, specifically the role of these mutations in the resistance to a second antibiotic after a first antibiotic gave rise to a specific mutation (where V139F was found in strains resistant to tetracycline, which previously acquired resistance to amoxicillin, enrofloxacin or kanamycin) [116].…”

Section: Mutations In Mexy-pa (K79 G287) Increase Aminoglycoside Resistancementioning

confidence: 99%

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Zwama

Nishino

2021

Antibiotics

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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.

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Section: Mutations In Mexy-pa (K79 G287) Increase Aminoglycoside Resistancementioning

confidence: 99%

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Zwama

Nishino

2021

Antibiotics

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“…The basal efflux present in bacterial cells is essentially the first mechanism with membrane impermeability that faces antibiotics in clinical isolates [ 14 , 15 , 16 ]. The basal activity is not clinically detected in a wild strain, although various stimuli are able to quickly initiate their overexpression and synthesis.…”

Section: Clinical Impact Situationmentioning

confidence: 99%

“…Although not detected in routine, the efflux paves the way for the most radical mechanisms of resistance [ 3 ]. A sub-inhibitory intracellular concentration of the antibiotic then promotes the development or acquisition of more specific mechanisms of resistance-like enzymatic responses or target mutations [ 15 , 16 ]. For example, several mutations are found in genes, gyrA and parC , coding the gyrase target and they are frequently associated with efflux resulting in high MIC levels [ 17 ].…”

Section: Clinical Impact Situationmentioning

confidence: 99%

Clinical Status of Efflux Resistance Mechanisms in Gram-Negative Bacteria

2021

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Antibiotic efflux is a mechanism that is well-documented in the phenotype of multidrug resistance in bacteria. Efflux is considered as an early facilitating mechanism in the bacterial adaptation face to the concentration of antibiotics at the infectious site, which is involved in the acquirement of complementary efficient mechanisms, such as enzymatic resistance or target mutation. Various efflux pumps have been described in the Gram-negative bacteria most often encountered in infectious diseases and, in healthcare-associated infections. Some are more often involved than others and expel virtually all families of antibiotics and antibacterials. Numerous studies report the contribution of these pumps in resistant strains previously identified from their phenotypes. The authors characterize the pumps involved, the facilitating antibiotics and those mainly concerned by the efflux. However, today no study describes a process for the real-time quantification of efflux in resistant clinical strains. It is currently necessary to have at hospital level a reliable and easy method to quantify the efflux in routine and contribute to a rational choice of antibiotics. This review provides a recent overview of the prevalence of the main efflux pumps observed in clinical practice and provides an idea of the prevalence of this mechanism in the multidrug resistant Gram-negative bacteria. The development of a routine diagnostic tool is now an emergency need for the proper application of current recommendations regarding a rational use of antibiotics.

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“…AcrB functions as the inner membrane transporter using ATP to enable export, AcrA functions as the membrane fusion protein complexing with the other proteins to generate channels, and TolC functions as the outer membrane protein facilitating efflux outside the cell 85 . In practice, AcrR is a transcriptional repressor which was located upstream of the acrAB operon accounting for the management of this pump system, the deletion of AcrR could facilitate this efflux pump to transport geraniol to span the double-layer membrane into the media 86 .…”

Section: Transporter Engineeringmentioning

confidence: 99%

Metabolic engineering of microbes for monoterpenoid production

Zhu

Kong

Zhao

et al. 2021

Biotechnology Advances

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Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

Abstract: Combatting the rise of antibiotic resistance is a significant challenge. Efflux pumps are an important contributor to drug resistance; they exist across many cell types and can export numerous classes of antibiotics.

Cited by 18 publications

References 64 publications

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Clinical Status of Efflux Resistance Mechanisms in Gram-Negative Bacteria

Metabolic engineering of microbes for monoterpenoid production

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