In silico study of glycosylated antibiotics as new bacterial efflux pumps inhibitors

Antimicrobial resistance is considered a major concern problem; bacteria have evolved mechanisms to overcome antibiotics’ action through evolutionary process. One main resistance mechanism that bacteria developed is the pumping of the antibiotics out of bacterial cells by transmembrane transporter proteins known as efflux pumps. To overcome bacterial resistance guided by efflux pumps, one approach is using efflux pumps inhibitors (EPIs), small molecules that obstruct efflux pumps binding sites and its structural assembly leading to disability in the efflux pumps normal function, new EPIs which under the current study are created by modifying the chemical structure of antibiotics including Ampicillin, Penicillin, Chloramphenicol, Ciprofloxacin and Tetracycline, the modification includes adding N-acetyl glucose amine moiety to acceptor OH group of the respective antibiotic, the new antibiotics are glycosylated EPIs. To test the effectiveness of the new EPIs in inhibiting AcrB-TolC and MexA-OprM efflux pumps functions, ADME properties for all the glycosylated antibiotics have been measured through applying Lipinski’s role of 5, docking and simulation studies have been included as well. Interestingly, docked glycosylated tetracycline has given the highest binding energy with -9.4 against AcrB and -8.8 against MexA. The simulation study has confirmed the glycosylated tetracycline binding in the active sites of both pumps, as well as its stability during the biological dynamics of both pumps (opening and closing channels). However, we recommend further study’s validation through running a long simulation time of about 50 ns or more which was un applicable due to cost limitation.