The importance of efflux pumps in bacterial antibiotic resistance

Webber, Mark A.; Piddock, Laura J. V.

doi:10.1093/jac/dkg050

Cited by 638 publications

(410 citation statements)

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“…Comparitive genomics has identified a number of efflux transporters and some of these are classified as H + -antiporters. In Campylobacter spp., the resistance to nodulation and cell division (RND) family [176] is associated with high-level fluoroquinolone resistance [79,132,187]. This resistance is linked to the activation of the Campylobacter-mediated efflux system referred to as the cmeABC-operon.…”

Section: Mdr-mediated By Antimicrobial Efflux Systemsmentioning

confidence: 99%

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Campylobacter

et al. 2005

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-Species within the genus, Campylobacter, have emerged over the last three decades as significant clinical pathogens, particularly of human public health concern, where the majority of acute bacterial enteritis in the Western world is due to these organisms. Of particular concern are the species, C. jejuni and C. coli, which are responsible for most of these gastrointestinal-related infections. Although these organisms have already emerged as causative agents of zoonoses, several aspects of their epidemiology and pathophysiology are only beginning to emerge. Trends in increasing antibiotic resistance are beginning to emerge with oral antibiotics, which may be the drug of choice for when it is necessary to intervene chemotherapeutically. This review wishes to examine (i) emerging clinical aspects of the disease, such as Guillain Barré syndrome (GBS), (ii) the association between these organisms and poultry as a natural host, (iii) environmental aspects of Campylobacter epidemiology, (iv) the emergence of atypical campylobacters (v) emerging trends in antibiotic resistance, (vi) adoption of modern methods for the detection of campylobacters.

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Section: Mdr-mediated By Antimicrobial Efflux Systemsmentioning

confidence: 99%

“…Efflux mechanisms have an important impact on antimicrobial resistance [187]. Resistance by efflux can be easily disseminated [91].…”

Section: Mdr-mediated By Antimicrobial Efflux Systemsmentioning

confidence: 99%

Campylobacter

et al. 2005

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“…This probably occurs because efflux pump overexpression by itself is unable to express a high-level resistance phenotype. In contrast, the association of overexpression of these genes with other antimicrobial resistance mechanisms may confer not only high-level but also broad-spectrum resistance (Van Bambeke et al, 2003;Webber & Piddock, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…The AcrAB multidrug efflux system is the main efflux pump in Escherichia coli and belongs to the RND family. This multidrug efflux pump system is responsible for resistance to tetracycline, chloramphenicol, ampicillin, nalidixic acid and rifamicin (Moreira et al, 2004;Nikaido, 1996;Webber & Piddock, 2003).…”

Section: Introductionmentioning

confidence: 99%

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains

Marchetti

Errecalde

Mestorino

2012

Journal of Medical Microbiology

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The objective of this study was to evaluate the interaction of the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP) when combined with different families of antimicrobial agents against isogenic strains and multidrug-resistant (MDR) Escherichia coli field strains isolated from animals. Laboratory isogenic strains of E. coli with different levels of expression of efflux pumps were used as quality controls. Ten MDR E. coli strains were collected from healthy animals in a cross-sectional study in four commercial dairy farms. The MICs of florfenicol, ciprofloxacin, tetracycline and ampicillin were determined by a serial microdilution method in Luria-Bertani broth in the presence or absence of NMP. NMP used with ampicillin exerted no effect on the isogenic or field strains. In most of the field MDR E. coli strains and in an acrAB-overexpressing (AG112) isogenic strain, the MICs of florfenicol, ciprofloxacin and tetracycline decreased at least fourfold when the antimicrobial was combined with the highest NMP concentrations. In the wild-type strain (AG100), there were no decreases of more than twice the MIC, whilst in strain AG100A, an efflux pump-deficient strain, the MIC did not change, regardless of the concentration of NMP used with these three antimicrobials. Thus, ampicillin was not affected by the efflux pump mechanism, whereas ciprofloxacin, tetracycline and florfenicol were shown to be substrates of efflux pumps, with a consequent significant reduction in MICs. Resistance could not be completely reversed in the E. coli field strains by NMP, probably because other resistance mechanisms were also present. However, in strain AG112, the MIC results demonstrated that NMP expressed an important synergistic activity with florfenicol. The reduction in florfenicol MIC value was sufficient to reverse antimicrobial resistance completely for AG112.

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“…Third, a DCA may directly resist a drug through a molecular change or a change in receptors and/or drug transport. For instance, bacteria may indirectly resist antibiotics through the upregulation of efflux pumps [16], or directly resist via drug modification or inactivation [17]. Fourth, some individual agents may be less attainable by the drug than others, either due to spatial refuges or active escape through plastic behaviors.…”

Section: Dca Escapementioning

confidence: 99%

Six wedges to curing disease

Hochberg

2017

Preprint

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Abstract.One of the great challenges in ecology and evolutionary biology is to explain disease, whether caused by infectious agents such as parasites and pathogens, or by the deterioration or transformation of cellular behavior and function, a prime example of the latter being cancer. Decades of observation and research suggest that successfully treating disease requires insights into how the environment mediates the interactions between disease causing agents (DCAs) and diseased individuals. A major finding is that single factor, targeted therapies are not only likely to fail in controlling or eradicating many DCAs, but are also likely to select for resistance, reducing options for subsequent treatment attempts, and in cases of infectious DCAs, rendering therapeutic agents (e.g., antibiotics) obsolete.I argue that meeting the growing challenge of treating disease in agriculture and animal husbandry, in protected and domesticated species, wildlife, and in the human population will require a fundamental understanding of ecological interactions at sites of infection or disease. I discuss different ways in which components of such disease ecosystems mediate DCA and therapeutic dynamics and resistance evolution, and derive a very simple mathematical criterion for therapeutic success. I then touch on how fundamental insights as revealed by the processes of evolutionary rescue and competitive release can help understand why therapies succeed or fail. Finally, I present six "wedges" that can each contribute alone, or as part of multi-pronged approaches to successfully treating disease. The Magic BulletDespite remarkable progress in prevention and treatment, the impacts of diseases in agriculture and animal husbandry, and on protected and domesticated species, wildlife, and human health are likely to intensify into the 21 st century. Humans in particular are increasingly in contact with each other and with wildlife, treated with drug regimens that select for resistance, and adopt life-styles or are exposed to environments that render them more susceptible to infectious diseases and more likely to get cellular diseases such as cancers.For many clinicians the Holy Grail is to discover the Ehrlichian "Magic Bullet"-a drug that will target the disease-causing agents (DCAs) and cure disease. Intuitively, the most effective way to reduce DCAs is to "hit hard and fast". That is, more drug means more kill within the tolerance limits of the patient. Rapid administration of the drug means forestalling further DCA growth and associated symptoms, but also reducing the probability of the appearance of resistant mutant strains. Despite decades of research on pest and disease control (much of it with an ecological basis) this approach and the many alternatives described below remain highly controversial (e.g., [1]).The Magic Bullet may be shortsighted for another reason. What will cure most patients may not be optimal for the general population in which resistant variants may emerge and spread 1 . This problem is in many ways similar...

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The importance of efflux pumps in bacterial antibiotic resistance

Cited by 638 publications

References 30 publications

Campylobacter

Campylobacter

Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains

Six wedges to curing disease

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