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

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A Correction to this article was published on 22 May 2024

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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.

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References

  • Akash S, Abdelkrim G, Bayil I, Hosen ME, Mukerjee N, Shater AF, Saleh FM, Albadrani GM, Al-Ghadi MQ, Abdel‐Daim MM (2023a) Antimalarial drug discovery against malaria parasites through haplopine modification: an advanced computational approach. J Cell Mol Med

  • Akash S, Bayıl I, Hossain MS, Islam MR, Hosen ME, Mekonnen AB, Nafidi H-A, Bin Jardan YA, Bourhia M, Bin Emran T (2023b) Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by apigenin derivatives. Sci Rep 13:16565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akash S, Bibi S, Biswas P, Mukerjee N, Khan DA, Hasan MN, Sultana NA, Hosen ME, Jardan YA, Bin, Nafidi H-A (2023c) Revolutionizing anti-cancer drug discovery against breast cancer and lung cancer by modification of natural genistein: an advanced computational and drug design approach. Front Oncol 13:1228865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akash S, Hosen ME, Mahmood S, Supti SJ, Kumer A, Sultana S, Jannat S, Bayıl I, Nafidi H-A, Jardan10 YA Bin (2023d) Anti-parasitic drug discovery against Babesia microti by natural compounds: an extensive computational drug design approach. Front Cell Infect Microbiol 13:1222913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alhabbab RY, Alhabbab RY (2018) C-reactive protein (CRP) latex agglutination test. Basic Serol Test 59–62

  • An Q, Li C, Chen Y, Deng Y, Yang T, Luo Y (2020) Repurposed drug candidates for antituberculosis therapy. Eur J Med Chem 192:112175

    Article  CAS  PubMed  Google Scholar 

  • Areej S, Sattar A, Javeed A, Raza S (2021) Diphenhydramine and levofloxacin combination therapy against antimicrobial resistance in respiratory tract infections. Future Microbiol 16:409–420

    Article  CAS  PubMed  Google Scholar 

  • Askoura M, Mottawea W, Abujamel T, Taher I (2011) Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. Libyan J Med 6

  • Avakh A, Grant GD, Cheesman MJ, Kalkundri T, Hall S (2023) The art of War with Pseudomonas aeruginosa: Targeting Mex Efflux pumps directly to strategically enhance Antipseudomonal Drug Efficacy. Antibiotics 12:1304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Azad GK, Tomar RS (2014) Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways. Mol Biol Rep 41:4865–4879

    Article  CAS  PubMed  Google Scholar 

  • Barbarossa A, Rosato A, Corbo F, Clodoveo ML, Fracchiolla G, Carrieri A, Carocci A (2022) Non-antibiotic drug repositioning as an alternative antimicrobial approach. Antibiotics 11:816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhadra P, Siu SWI (2019) Refined empirical force field to model protein–self-assembled monolayer interactions based on AMBER14 and GAFF. Langmuir 35:9622–9633

    Article  CAS  PubMed  Google Scholar 

  • Chen D, Oezguen N, Urvil P, Ferguson C, Dann SM, Savidge TC (2016) Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci Adv 2:e1501240

    Article  PubMed  PubMed Central  Google Scholar 

  • Collins GT, Witkin JM, Newman AH et al (2005) Dopamine agonist-induced yawning in rats: a dopamine D3 receptor-mediated behavior. J Pharmacol Exp Ther 314:310–319

    Article  CAS  PubMed  Google Scholar 

  • Cui X, Wang L, Lue Y, Yue C (2022) Development and research progress of anti-drug resistant fungal drugs. J Infect Public Health

  • Dallakyan S, Olson AJ (2015) Small-molecule library screening by docking with PyRx. Chemical biology. Springer, pp 243–250

  • Davin-Regli A, Pages JM, Ferrand A (2021) Clinical status of efflux resistance mechanisms in gram-negative bacteria. Antibiotics 10

  • DeNicola DB (2011) Advances in hematology analyzers. Top Companion Anim Med 26:52–61

    Article  PubMed  Google Scholar 

  • Ding X, Yang C, Moreira W, Yuan P, Periaswamy B, de Sessions PF, Zhao H, Tan J, Lee A, Ong KX (2020) A macromolecule reversing antibiotic resistance phenotype and repurposing drugs as potent antibiotics. Adv Sci 7:2001374

    Article  CAS  Google Scholar 

  • Domínguez AV, Mejías MEJ, Smani Y (2020) Drugs repurposing for multi-drug resistant bacterial infections. Drug Repurposing Hypothesis Mol Asp Ther Appl

  • Doyno C, Sobieraj DM, Baker WL (2021) Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose. Clin Toxicol 59:12–23

    Article  CAS  Google Scholar 

  • Elshikh M, Ahmed S, Funston S, Dunlop P, McGaw M, Marchant R, Banat IM (2016) Resazurin-based 96-well plate microdilution method for the determination of minimum inhibitory concentration of biosurfactants. Biotechnol Lett 38:1015–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiolet T, Guihur A, Rebeaud M, Mulot M, Peiffer-Smadja N, Mahamat-Saleh Y (2020) Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis. Clin Microbiol Infect 27:19–27

    Article  PubMed  PubMed Central  Google Scholar 

  • Foletto VS, da Rosa TF, Serafin MB et al (2021) Repositioning of non-antibiotic drugs as an alternative to microbial resistance: a systematic review. Int J Antimicrob Agents 58

  • Gautret P, Lagier J-C, Parola P, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 56:105949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghahremanian S, Rashidi MM, Raeisi K, Toghraie D (2022) Molecular dynamics simulation approach for discovering potential inhibitors against SARS-CoV-2: a structural review. J Mol Liq 354:118901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghiselli R, Giacometti A, Cirioni O et al (2002) Quinupristin/dalfopristin bonding in combination with intraperitoneal antibiotics prevent infection of knitted polyester graft material in a subcutaneous rat pouch model infected with resistant Staphylococcus epidermidis. Eur J Vasc Endovasc Surg 24:230–234

    Article  CAS  PubMed  Google Scholar 

  • Gill EE, Franco OL, Hancock REW (2015) Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens. Chem Biol Drug Des 85:56–78

    Article  CAS  PubMed  Google Scholar 

  • Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss‐pdb viewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  CAS  PubMed  Google Scholar 

  • GUPTA P, RAI N, GAUTAM P (2015) Anticancer drugs as potential inhibitors of AcrAB-TolC of multidrug resistant Escherichia coli: an in silico molecular modeling and docking study. Anticancer DRUGS 8

  • Harrach MF, Drossel B (2014) Structure and dynamics of TIP3P, TIP4P, and TIP5P water near smooth and atomistic walls of different hydroaffinity. J Chem Phys 140:174501

    Article  PubMed  Google Scholar 

  • Hegazy WAH, Rajab AAH, Lila ASA, Abbas HA (2021) Anti-diabetics and antimicrobials: Harmony of mutual interplay. World J Diabetes 12:1832

    Article  PubMed  PubMed Central  Google Scholar 

  • Hollingsworth SA, Dror RO (2018) Molecular dynamics simulation for all. Neuron 99:1129–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosen ME, Rahman MS, Faruqe MO, Khalekuzzaman M, Islam MA, Acharjee UK, Zaman R (2023) Molecular docking and dynamics simulation approach of Camellia sinensis leaf extract derived compounds as potential cholinesterase inhibitors. Silico Pharmacol 11:14

    Article  Google Scholar 

  • Huang Y, Chen W, Wallace JA, Shen J (2016) All-atom continuous constant pH molecular dynamics with particle mesh Ewald and titratable water. J Chem Theory Comput 12:5411–5421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jampilek J (2022) Drug repurposing to overcome microbial resistance. Drug Discov Today 27:2028–2041

    Article  CAS  PubMed  Google Scholar 

  • Jeong YS, Jusko WJ (2021) Meta-assessment of metformin absorption and disposition pharmacokinetics in nine species. Pharmaceuticals 14

  • Kamurai B, Mombeshora M, Mukanganyama S (2020) Repurposing of drugs for antibacterial activities on selected ESKAPE bacteria Staphylococcus aureus and Pseudomonas aeruginosa. Int J Microbiol 2020

  • Kaul G, Shukla M, Dasgupta A, Chopra S (2019) Update on drug-repurposing: is it useful for tackling antimicrobial resistance? Future Microbiol 14:829–831

    Article  CAS  PubMed  Google Scholar 

  • Koh **g Jie A, Hussein M, Rao GG, Li J, Velkov T (2022) Drug repurposing approaches towards defeating multidrug-resistant gram-negative pathogens: novel polymyxin/non-antibiotic combinations. Pathogens 11:1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar A, Alam A, Grover S, Pandey S, Tripathi D, Kumari M, Rani M, Singh A, Akhter Y, Ehtesham NZ (2019) Peptidyl-prolyl isomerase-B is involved in Mycobacterium tuberculosis biofilm formation and a generic target for drug repurposing-based intervention. Npj Biofilms Microbiomes 5:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Jia Y, Yang K, Li R, **ao X, Zhu K, Wang Z (2020) Metformin restores tetracyclines susceptibility against multidrug resistant bacteria. Adv Sci 7:1902227

    Article  CAS  Google Scholar 

  • Masadeh MM, Alzoubi KH, Masadeh MM, Aburashed ZO (2021) Metformin as a potential adjuvant antimicrobial agent against multidrug resistant bacteria. Clin Pharmacol Adv Appl 83–90

  • Miró-Canturri A, Ayerbe-Algaba R, Smani Y (2019) Drug repurposing for the treatment of bacterial and fungal infections. Front Microbiol 10:41

    Article  PubMed  PubMed Central  Google Scholar 

  • Mohammad Sadeghi H, Adeli I, Mousavi T, Daniali M, Nikfar S, Abdollahi M (2021) Drug Repurposing for the management of Depression. Where Do We Stand Currently? Life 11:774

    CAS  PubMed  Google Scholar 

  • Mor A, Ziv G, Levy Y (2008) Simulations of proteins with inhomogeneous degrees of freedom: the effect of thermostats. J Comput Chem 29:1992–1998

    Article  CAS  PubMed  Google Scholar 

  • Mor A, Petersen I, Sørensen HT, Thomsen RW (2016) Metformin and other glucose-lowering drug initiation and rates of community-based antibiotic use and hospital-treated infections in patients with type 2 diabetes: a Danish nationwide population-based cohort study. BMJ Open 6:e011523

    Article  PubMed  PubMed Central  Google Scholar 

  • Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56–67

    Article  CAS  PubMed  Google Scholar 

  • Oyedara OO, Fadare OA, Franco-Frías E, Heredia N, García S (2023) Computational assessment of phytochemicals of medicinal plants from Mexico as potential inhibitors of Salmonella enterica efflux pump AcrB protein. J Biomol Struct Dyn 41:1776–1789

    Article  CAS  PubMed  Google Scholar 

  • Ranjbar R, Farahani A (2019) Shigella: antibiotic-resistance mechanisms and new horizons for treatment. Infect Drug Resist 12:3137–3167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ronco T, Jørgensen NS, Holmer I, Kromann S, Sheikhsamani E, Permin A, Svenningsen SW, Christensen JB, Olsen RH (2020) A novel promazine derivative shows high in vitro and in vivo antimicrobial activity against Staphylococcus aureus. Front Microbiol 11:560798

    Article  PubMed  PubMed Central  Google Scholar 

  • Rose PW, Bi C, Bluhm WF, Christie CH, Dimitropoulos D, Dutta S, Green RK, Goodsell DS, Prlić A, Quesada M (2012) The RCSB Protein Data Bank: new resources for research and education. Nucleic Acids Res 41:D475–D482

    Article  PubMed  PubMed Central  Google Scholar 

  • Salsbury FR Jr (2010) Molecular dynamics simulations of protein dynamics and their relevance to drug discovery. Curr Opin Pharmacol 10:738–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandberg A, Hessler JHR, Skov RL, Blom J, Frimodt-Møller N (2009) Intracellular activity of antibiotics against Staphylococcus aureus in a mouse peritonitis model. Antimicrob Agents Chemother 53:1874–1883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, Pos KM (2006) Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Sci (80-) 313:1295–1298

    Article  CAS  Google Scholar 

  • Shaheen A, Iqbal M, Mirza O, Rahman M (2017) Structural biology meets drug resistance: an overview on multidrug resistance transporters. J Indian Inst Sci 97:165–175

    Article  Google Scholar 

  • Shaikh SS, Bawazir AS, Yahya BA (2022) Phytochemical, histochemical and in vitro antimicrobial study of various solvent extracts of costus speciosus (j. koenig) sm. And costus pictus d. don. Turkish J Pharm Sci 19:145

    Article  CAS  Google Scholar 

  • Silva-Santana G, Bax JC, Fernandes DCS, Bacellar DTL, Hooper C, Dias AASO, Silva CB, de Souza AM, Ramos S, Santos RA (2020) Clinical hematological and biochemical parameters in Swiss, BALB/c, C57BL/6 and B6D2F1 Mus musculus. Anim Model Exp Med 3:304–315

    Article  Google Scholar 

  • Singhal A, Jie L, Kumar P, Hong GS, Leow MK-S, Paleja B, Tsenova L, Kurepina N, Chen J, Zolezzi F (2014) Metformin as adjunct antituberculosis therapy. Sci Transl Med 6:263ra159–263ra159

    Article  PubMed  Google Scholar 

  • Thakare R, Kaul G, Shukla M, Kesharwani P, Srinivas N, Dasgupta A, Chopra S (2020) Repurposing nonantibiotic drugs as antibacterials. Drug Discovery Targeting Drug-resistant Bacteria. Elsevier, pp 105–138

  • Theuretzbacher U, Outterson K, Engel A, Karlén A (2020) The global preclinical antibacterial pipeline. Nat Rev Microbiol 18:275–285

    Article  PubMed  Google Scholar 

  • Vargiu AV, Nikaido H (2012) Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Natl Acad Sci 109:20637–20642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • **ao Y, Liu F, Li S, Jiang N, Yu C, Zhu X, Qin Y, Hui J, Meng L, Song C (2020) Metformin promotes innate immunity through a conserved PMK-1/p38 MAPK pathway. Virulence 11:39–48

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Rajshahi, Rajshahi, 6205, Bangladesh

    Showna Hossain, Rafat Hossain Rafi, Md. Rafiqul Islam Khan, Md. Eram Hosen, Md. Khademul Islam Molla, Md. Omar Faruqe, Md. Abdul Alim Al-Bari & Somlal Das

  2. School of Pharmacy, BRAC University, Dhaka, Bangladesh

    Farhana Alam Ripa

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  1. Showna Hossain
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  2. Rafat Hossain Rafi
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  3. Farhana Alam Ripa
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  4. Md. Rafiqul Islam Khan
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  5. Md. Eram Hosen
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  6. Md. Khademul Islam Molla
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  7. Md. Omar Faruqe
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  8. Md. Abdul Alim Al-Bari
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  9. Somlal Das
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Contributions

SH: Conception, design of the work RHR: Data Acquisition, analysis FR: Design of the work, acquisition Md. RIK: Interpretation of data EH: Data analysis KIM: Drafted the work, revised the work OF: Data analysis, interpretation of data, draft AAAB: Data analysis, interpretation of data, revise SD: Edit, Modifiation, Review.

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Correspondence to Md. Omar Faruqe or Md. Abdul Alim Al-Bari.

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Communicated by Yusuf Akhter.

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Hossain, S., Rafi, R.H., Ripa, F.A. et al. Modulating the antibacterial effect of the existing antibiotics along with repurposing drug metformin. Arch Microbiol 206, 190 (2024). https://doi.org/10.1007/s00203-024-03917-5

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