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The search of potential inhibitors of the AcrAB-TolC system of multidrug-resistant Escherichia coli: an in silico approach.
Appl Microbiol Biotechnol 2019; 103(15):6309-6318AM

Abstract

The number of infections caused by multidrug antibiotic resistance (MDR) species is increasing globally. The efflux pump system, AcrAB-TolC, confers Escherichia coli resistance to many antibiotics and results in poor treatment outcomes. Different rational drug design techniques were employed to search for a safe and effective AcrAB-TolC system inhibitor. Ligand docking was performed to analyze the binding of different ArcB substrates and/or inhibitors in the different AcrAB crystal structure binding sites. The validated docking site using the established docking preferences was used to perform virtual high-throughput screening on a large library of compounds. Domperidone, a known and safe over-the-counter antiemetic drug, was proposed as an effective ArcB inhibitor. Microbiological studies confirmed the computational results and domperidone reversed the resistance to the antibiotics: levofloxacin and ciprofloxacin in the MDR E. coli stains with an effect that surpassed the effect of the known efflux pump inhibitor, reserpine. In addition, it was able to increase both antibiotic effects on susceptible strains. This finding suggests that the antibiotic-domperidone combination can be used clinically to treat infections caused by multidrug-resistant E. coli strains.

Authors+Show Affiliations

Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, 11196, Jordan. habdelhalim@uop.edu.jo.Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, 11196, Jordan.Faculty of Science, Taibah University, Almadinah Almunawarrah, Saudi Arabia.Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31209525

Citation

Abdel-Halim, Heba, et al. "The Search of Potential Inhibitors of the AcrAB-TolC System of Multidrug-resistant Escherichia Coli: an in Silico Approach." Applied Microbiology and Biotechnology, vol. 103, no. 15, 2019, pp. 6309-6318.
Abdel-Halim H, Al Dajani A, Abdelhalim A, et al. The search of potential inhibitors of the AcrAB-TolC system of multidrug-resistant Escherichia coli: an in silico approach. Appl Microbiol Biotechnol. 2019;103(15):6309-6318.
Abdel-Halim, H., Al Dajani, A., Abdelhalim, A., & Abdelmalek, S. (2019). The search of potential inhibitors of the AcrAB-TolC system of multidrug-resistant Escherichia coli: an in silico approach. Applied Microbiology and Biotechnology, 103(15), pp. 6309-6318. doi:10.1007/s00253-019-09954-1.
Abdel-Halim H, et al. The Search of Potential Inhibitors of the AcrAB-TolC System of Multidrug-resistant Escherichia Coli: an in Silico Approach. Appl Microbiol Biotechnol. 2019;103(15):6309-6318. PubMed PMID: 31209525.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The search of potential inhibitors of the AcrAB-TolC system of multidrug-resistant Escherichia coli: an in silico approach. AU - Abdel-Halim,Heba, AU - Al Dajani,Ala'a, AU - Abdelhalim,Abeer, AU - Abdelmalek,Suzanne, Y1 - 2019/06/17/ PY - 2019/04/01/received PY - 2019/05/28/accepted PY - 2019/05/09/revised PY - 2019/6/19/pubmed PY - 2019/11/21/medline PY - 2019/6/19/entrez KW - AcrAB–TolC KW - Antibiotic resistance KW - Efflux pump KW - Efflux pump inhibitor KW - Ligand docking KW - Virtual high-throughput screening SP - 6309 EP - 6318 JF - Applied microbiology and biotechnology JO - Appl. Microbiol. Biotechnol. VL - 103 IS - 15 N2 - The number of infections caused by multidrug antibiotic resistance (MDR) species is increasing globally. The efflux pump system, AcrAB-TolC, confers Escherichia coli resistance to many antibiotics and results in poor treatment outcomes. Different rational drug design techniques were employed to search for a safe and effective AcrAB-TolC system inhibitor. Ligand docking was performed to analyze the binding of different ArcB substrates and/or inhibitors in the different AcrAB crystal structure binding sites. The validated docking site using the established docking preferences was used to perform virtual high-throughput screening on a large library of compounds. Domperidone, a known and safe over-the-counter antiemetic drug, was proposed as an effective ArcB inhibitor. Microbiological studies confirmed the computational results and domperidone reversed the resistance to the antibiotics: levofloxacin and ciprofloxacin in the MDR E. coli stains with an effect that surpassed the effect of the known efflux pump inhibitor, reserpine. In addition, it was able to increase both antibiotic effects on susceptible strains. This finding suggests that the antibiotic-domperidone combination can be used clinically to treat infections caused by multidrug-resistant E. coli strains. SN - 1432-0614 UR - https://www.unboundmedicine.com/medline/citation/31209525/The_search_of_potential_inhibitors_of_the_AcrAB-TolC_system_of_multidrug-resistant_Escherichia_coli:_an_in_silico_approach L2 - https://dx.doi.org/10.1007/s00253-019-09954-1 DB - PRIME DP - Unbound Medicine ER -