The search of potential inhibitors of the AcrAB–TolC system of multidrug-resistant Escherichia coli: an in silico approach

• Published in: Applied microbiology and biotechnology Vol. 103; no. 15; pp. 6309 - 6318
• Main Authors: Abdel-Halim, Heba, Al Dajani, Ala’a, Abdelhalim, Abeer, Abdelmalek, Suzanne
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2019; Springer; Springer Nature B.V
• Subjects: Antibiotic resistance; Antibiotics; Antiemetics; Bacteria; Binding sites; Biomedical and Life Sciences; Biotechnology; Carrier proteins; Ciprofloxacin; Computer applications; Crystal structure; Crystals; Docking; Drug development; E coli; Efflux; Escherichia coli; Genetic aspects; High-throughput screening; Identification and classification; Inhibitors; Levofloxacin; Life Sciences; Methods and Protocols; Microbial Genetics and Genomics; Microbiological studies; Microbiology; Multidrug resistance; Multidrug resistant organisms; Properties; Reserpine; Structure; Substrate inhibition; Saudi Arabia; Jordan; Ligand docking; Efflux pump inhibitor; Virtual high-throughput screening; Efflux pump; Antibiotic resistance; AcrAB–TolC
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-019-09954-1

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.