Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors

Willers, Clarissa; Wentzel, Johannes F.; Plessis, Lissinda H. Du; Gouws, Chrisna; Hamman, Josias H.

doi:10.1080/14728222.2017.1265105

Cited by 41 publications

(34 citation statements)

References 155 publications

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“…The aryl-piperazine resulted in a ≥4-fold reduction in MIC of >50% of the isolates. However, NMP have faced limited success as EPIs due to its high toxicity at effective doses [82].…”

Section: Epis and Their Potential Role In Biofilm Disruption In E Colimentioning

confidence: 99%

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

2019

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Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens (Enterococcus faecium., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli), in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

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“…The aryl-piperazine resulted in a ≥4-fold reduction in MIC of >50% of the isolates. However, NMP have faced limited success as EPIs due to its high toxicity at effective doses [82].…”

Section: Epis and Their Potential Role In Biofilm Disruption In E Colimentioning

confidence: 99%

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

2019

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“…For example, efflux pump inhibitors reserpine, verapamil, 2,4-dinitrophenol (DNP) and pyrrole derivatives have been shown to increase the susceptibility to norfloxacin, RIF and INH by inhibiting efflux pumps (i.e., Rv1258c and MmpL3), in drug-susceptible mycobacteria (Sharma et al, 2010; World Health Organization, 2011; La Rosa et al, 2012; Machado et al, 2012; Willers et al, 2017). Another efflux pump inhibitor is a mammalian efflux pump inhibitor, timcodar (Nasiri et al, 2016).…”

Section: Drug Resistance Mechanisms In Mycobacteriamentioning

confidence: 99%

New Insights in to the Intrinsic and Acquired Drug Resistance Mechanisms in Mycobacteria

et al. 2017

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Infectious diseases caused by clinically important Mycobacteria continue to be an important public health problem worldwide primarily due to emergence of drug resistance crisis. In recent years, the control of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (MTB), is hampered by the emergence of multidrug resistance (MDR), defined as resistance to at least isoniazid (INH) and rifampicin (RIF), two key drugs in the treatment of the disease. Despite the availability of curative anti-TB therapy, inappropriate and inadequate treatment has allowed MTB to acquire resistance to the most important anti-TB drugs. Likewise, for most mycobacteria other than MTB, the outcome of drug treatment is poor and is likely related to the high levels of antibiotic resistance. Thus, a better knowledge of the underlying mechanisms of drug resistance in mycobacteria could aid not only to select the best therapeutic options but also to develop novel drugs that can overwhelm the existing resistance mechanisms. In this article, we review the distinctive mechanisms of antibiotic resistance in mycobacteria.

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“…71 Increasing numbers of review articles during the past few years speak clearly about the increasing interest in this field of research. 1,20,[72][73][74][75] The present article is focused on the currently known EPIs and explores, where possible, the SAR of each individual family of EPIs in the most typical and extensively studied WHO priority pathogens (S. aureus, E. coli, and P. aeruginosa), together with their corresponding MDR efflux systems NorA, AcrAB-TolC, and MexAB-OprM. The most significant achievements are here summarized and knowledge concerning recent advances in the research on EPIs upgraded.…”

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confidence: 99%

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

145

116

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Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug‐resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB‐TolC in Escherichia coli, and MexAB‐OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure‐activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead‐likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.

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Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors

Cited by 41 publications

References 155 publications

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

New Insights in to the Intrinsic and Acquired Drug Resistance Mechanisms in Mycobacteria

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

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