[Frontiers in Bioscience, Landmark, 22, 732-756, January 1, 2017]

Cellular efflux transporters and the potential role of natural products in combating efflux mediated drug resistance

Muhammad Ayaz 1 , Fazal Subhan 2 , Abdul Sadiq 1 , Farhat Ullah 1 , Jawad Ahmed 3 , Robert D. E. Sewell 4

1Department of Pharmacy, University of Malakand, Khyber Pakhtunkhwa (KP) 18000, Pakistan, 2Department of Pharmacy, University of Peshawar, Peshawar, Pakistan, 3Institute of Basic Medical Sciences (IBMS), Khyber Medical University (KMU) Peshawar, Pakistan, 4Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF103NU, U.K


1. Abstract
2. Introduction
3. ABC transporter proteins
    3.1. Mammalian ABC transporters and drug resistance
      3.1.1. Multidrug resistant (MDR) drug-transporting P-glycoprotein (ABCB1)
      3.1.2. Multidrug resistance associated Protein 1 (MRP1 or ABCC1)
      3.1.3. Multidrug resistance protein 2 (MRP2 or ABCC2)
      3.1.4. Multidrug resistance protein 3 (MRP3 or ABCC3)
      3.1.5. Multidrug resistance protein 4 (MRP4 or ABCC4)
      3.1.6. Multidrug resistance protein 5 (MRP5 or ABCC5)
      3.1.7. Breast cancer resistance proteins (BCRP or ABCG2)
    3.2. ABC transporter proteins and antibacterial drug resistance
    3.3. ABC transporter proteins and antifungal drug resistance
    3.4. ABC transporter proteins and parasitic drug resistance
4. Major facilitator superfamily (MFS)
5. Small multidrug resistance (SMR) superfamily
6. Multidrug and toxic compound extrusion (MATE) superfamily
    6.1. Bacterial MATEs
    6.2. Fungal MATEs
    6.3. Mammalian MATEs
7. Resistance nodulation division (RND) superfamily
8. Bacterial efflux pump inhibitors (EPIs)
9. Efflux pump inhibitors from natural sources
10. Conclusion
11. References


Efflux mediated multidrug resistance (MDR) is a major problem in the treatment of bacterial, fungal and protozoal infections in addition to cancer chemotherapy. Among other well known mechanisms, efflux pumps are significant contributors to chemo-resistance. Efflux mediated resistance generally occurs through up-regulation of genes responsible for the expression of transporter proteins extruding drugs from the cell to create intracellular sub-therapeutic concentrations leading to resistance. The rapid expansion of MDR pathogens necessitates the discovery of resistance modifying drugs, which in combination with antimicrobial or chemotherapeutic agents would tend to reinstate the action of these drugs and avert the emergence of acquired resistance. This review describes the existence of efflux pumps in prokaryotes and eukaryotes as well as their role in chemo-resistance with a special focus on natural product-derived efflux pump inhibitors.


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Abbreviations: AAHS (Aromatic acid H+ symporter), ABC (ATP binding cassette), ACS (Anion-cation symporter), ATP (Adenosine tri-phosphate), BCRP (Breast cancer resistance proteins), EPIs (Efflux pump inhibitors), FGHS (Fructose-glucose-galactose H+ symporters), MATE (Multidrug and toxic compound extrusion), MCP (Monocarboxylate porter), MDR (Multiple drug resistance/resistance), MFS (Major facilitator superfamily), MHS (Metabolites H+ symporters), MRP (Multidrug resistance protein), MRSA (Methicillin resistant Staphylococcus aureus), NHS (Nucleoside H+ symporter), NNP (Nitrate-nitrate porter), OFA (Oxalate/formate antiporter), OHS (Oligosaccharide H+ symporters), OPA (Organophosphate antiporters), P-gp (p-glycoprotein), PHS (Phosphate H+ symporter), POT (Proton dependent oligopeptide transporter), RND (Resistance nodulation division), SDR (Single drug resistance/resistant), SHS (Sialate/H+ symporter), SMR (Small multidrug resistance), SP (Sugar porter), UMFS (Unknown major facilitator superfamily).

Key Words: Efflux Pumps, EPIs, Natural Products, Chemo-resistance, MDR, Infectious Diseases, Review

Send correspondence to: Muhammad Ayaz, Department of Pharmacy, University of Malakand, Khyber Pakhtoonkhwa, (KPK) 18000, Pakistan, Tel: 92-346-8004990, Fax: +92-945-761627, E-mail: ayazuop@gmail.com