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Efflux pump inhibitors: new updates

Pharmacological Reports volume 73, pages 1–16 (2021)Cite this article

Abstract

The discovery of antibiotics ought to have ended the issue of bacterial infections, but this was not the case as it has led to the evolution of various mechanisms of bacterial resistance against various antibiotics. The efflux pump remains one of the mechanisms through which organisms develop resistance against antibiotics; this is because organisms can extrude most of the clinically relevant antibiotics from the interior cell environment to the exterior environment via the efflux pumps. Efflux pumps are thought to contribute significantly to biofilm formation as highlighted by various studies. Therefore, the inhibition of these efflux pumps can be a potential way of improving the activity of antibiotics, particularly now that the discovery of novel antibiotics is becoming tedious. Efflux pump inhibitors (EPIs) are molecules that can inhibit efflux pumps; they have been considered potential therapeutic agents for rejuvenating the activity of antibiotics that have already lost their activity against bacteria. However, studies are yet to determine the specific substrates for such pumps; the effect of altered efflux activity of these pumps on biofilm formation is still being investigated. A clear knowledge of the involvement of efflux pumps in biofilm development could aid in developing new agents that can interfere with their function and help to prevent biofilms formation; thereby, improving the outcome of treatment strategies. This review focuses on the novel update of EPIs and discusses the evidence of the roles of efflux pumps in biofilm formation; the potential approaches towards overcoming the increasing problem of biofilm-based infections are also discussed.

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Abbreviations

EPIs:

Efflux pump inhibitors

AMR:

Antimicrobial resistance

HGT:

Horizontal gene transfer

MDR:

Multidrug resistant

EPs:

Efflux pumps

ABC:

ATP-binding cassette

CCCP:

Carbonyl cyanide m-chlorophenylhydrazine

OMF:

Outer membrane factor

NOV:

Novobiocin

ERY:

Erythromycin

aPDI:

Antimicrobial photodynamic inactivation

PS:

Photosensitive dyes

MB:

Methylene blue

EPI-MB:

Efflux pump inhibitor-methylene blue

TBO:

Toluidine blue O

PABN:

Phenylalanine-arginine β-naphthylamide

SMR:

Small multidrug resistance

MATE:

Multidrug and toxin extrusion

MFS:

Major facilitator superfamily

RND:

Resistance-nodulation division

PMF:

Proton motive force

DARPin:

Designed ankyrin repeat proteins

WT:

Wild type

OM:

Outer membrane

MPC:

The minimal potentiating concentration

Et-Br:

Ethidium bromide

EPSs:

Extracellular polymeric substances

QQ:

Quorum quenching

CR:

Carbapenem resistant

WHO:

World Health Organization

NMP:

1-(1-Napthylmethyl) piperazine

NCE:

New chemical entity

ND:

Not determined

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Acknowledgements

The authors would like to thank Faculty of Industrial Sciences and Technology (FIST), Universiti Malaysia Pahang (UMP) for technical assistance for this article. Moreover, financial support from grant number (FRGS) RDU190163 is highly acknowledged and appreciated.

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Affiliations

  1. Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang (UMP), 26300, Gambang, Kuantan, Malaysia

    Manaf AlMatar & Essam A. Makky

  2. Department of Biotechnology, Institute of Natural and Applied Sciences (Fen Bilimleri Enstitüsü), Çukurova University, Adana, Turkey

    Osman Albarri

  3. Department of Medical Microbiology, Faculty of Medicine, Çukurova University, Adana, Turkey

    Fatih Köksal

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  1. Manaf AlMatar
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AlMatar, M., Albarri, O., Makky, E.A. et al. Efflux pump inhibitors: new updates. Pharmacol. Rep 73, 1–16 (2021). https://doi.org/10.1007/s43440-020-00160-9

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  • DOI: https://doi.org/10.1007/s43440-020-00160-9

Keywords

  • Efflux pump inhibitors
  • Antimicrobial resistance
  • Biofilm
  • Bacterial infection