Modulating the antibacterial effect of the existing antibiotics along with repurposing drug metformin.

ABSTRACT

Owing to the extensive prevalence of resistant bacteria to numerous antibiotic classes, antimicrobial resistance (AMR) poses a well-known hazard to world health. As an alternate approach in the field of antimicrobial drug discovery, repurposing the available medications which are also called antibiotic resistance breakers has been pursued for the treatment of infections with antimicrobial resistance pathogens. In this study, we used Haloperidol, Metformin and Hydroxychloroquine as repurposing drugs in in vitro (Antibacterial Antibiotic Sensitivity Test and Minimum Inhibitory Concentration-MIC) and in vivo (Shigellosis in Swiss albino mice) tests in combination with traditional antibiotics (Oxytetracycline, Erythromycin, Doxycycline, Gentamicin, Ampicillin, Chloramphenicol, and Penicillin) against a group of AMR resistance bacteria (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Shigella boydii). After observing the results of the conducted in vitro experiments we studied the effects of the above non antibiotic drugs in combination with the said antibiotics. As an repurposing adjuvant antibiotic drug, Metformin exhibited noteworthy activity in almost all in vitro, in vivo and in silico tests (Zone of inhibition for 30 to 43 mm for E.coli in combination with Doxycycline; MIC value decreased 50 µM to 0.781 µM with Doxycycline on S. boydii).In rodents Doxycycline and Metformin showed prominent against Shigellosis in White blood cell count (6.47 ± 0.152 thousand/mm3) and Erythrocyte sedimentation rate (10.5 ± 1.73 mm/hr). Our findings indicated that Metformin and Doxycycline combination has a crucial impact on Shigellosis. The molecular docking study was performed targeting the Acriflavine resistance protein B (AcrB) (PDB ID 4CDI) and MexA protein (PDB ID 6IOK) protein with Metformin (met8) drug which showed the highest binding energy with - 6.4 kcal/mol and - 5.5 kcal/mol respectively. Further, molecular dynamics simulation revealed that the docked complexes were relatively stable during the 100 ns simulation period. This study suggest Metformin and other experimented drugs can be used as adjuvants boost up antibiosis but further study is needed to find out the safety and efficacy of this non-antibiotic drug as potent antibiotic adjuvant.