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Research Article Open access CC BY 4.0

Glycosylated Antibiotics: New Promising Bacterial Efflux Pumps Inhibitors

Zahraa Ali Kamaz, Haruna Isiyaku Umar, Parth Doshi, Praveenya Suri

Microbiology Research Journal International · pp. 48–59 · Published 5 Apr 2024

10.9734/mrji/2024/v34i31435

Abstract

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, efflux pumps inhibitors (EPIs) are 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 most common antibiotics including Ampicillin, Penicillin, Chloramphenicol, Ciprofloxacin and Tetracycline, such antibiotics are modified by adding N-acetyl glucose amine moiety to acceptor OH group of the respective antibiotic, the newly modified 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 of glycosylated antibiotics have been measured through applying Lipinski’s role of 5, docking and simulation studies have been included as well. Docked glycosylated tetracycline has given the highest binding energy in the active sites of both pumps, with -9.4 against AcrB and -8.8 against MexA. The simulation study has confirmed the binding of the glycosylated tetracycline in the active sites of both pumps, as well as its stability during the biological dynamicity of both pumps (opening and closing channels). The results validation requires a long simulation time about 50 ns or more which was un applicable due to cost limitation, however, the newly glycosylated antibiotics have promising results that might make it eligible as drug candidates to overcome bacterial resistance.

Antibiotics MD simulation molecular docking efflux pumps inhibitors resistant bacteria

References (40)

  1. 1 AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading [DOI]
  2. 2 Molecular Properties That Influence the Oral Bioavailability of Drug Candidates [DOI]
  3. 3 Enhanced sampling techniques in molecular dynamics simulations of biological systems [DOI]
  4. 4 Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants [DOI]
  5. 5 Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm [DOI]
  6. 6 Role of bacterial efflux pumps in biofilm formation [DOI]
  7. 7 Efflux pump inhibitors for bacterial pathogens [DOI]
  8. 8 Back to Nature: Medicinal Plants as Promising Sources for Antibacterial Drugs in the Post-Antibiotic Era [DOI]
  9. 9 Drug transport mechanism of the AcrB efflux pump [DOI]
  10. 10 The Glycylcyclines [DOI]
  11. 11 Understanding drug‐likeness [DOI]
  12. 12 Bacterial efflux systems and efflux pumps inhibitors [DOI]
  13. 13 Inhibitors of efflux pumps in Gram-negative bacteria [DOI]
  14. 14 The Rule of Five for Non-Oral Routes of Drug Delivery: Ophthalmic, Inhalation and Transdermal [DOI]
  15. 15 Inhibitors of Bacterial Efflux Pumps as Adjuvants in Antibiotic Treatments and Diagnostic Tools for Detection of Resistance by Efflux [DOI]
  16. 16 Microbial Efflux Pump Inhibition: Tactics and Strategies [DOI]
  17. 17 Structures of the wild-type MexAB–OprM tripartite pump reveal its complex formation and drug efflux mechanism [DOI]
  18. 18 Current Advances in Developing Inhibitors of Bacterial Multidrug Efflux Pumps [DOI]
  19. 19 Towards understanding promiscuity in multidrug efflux pumps [DOI]
  20. 20 Comparison of structure- and ligand-based scoring functions for deep generative models: a GPCR case study [DOI]
  21. 21 Promising bactericidal approach of dihydrazone analogues against bio-film forming Gram-negative bacteria and molecular mechanistic studies [DOI]
  22. 22 Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs [DOI]
  23. 23 Effect of Low Charge and High Hydrophobicity on Antimicrobial Activity of the Quinazolinone-Peptide Conjugates [DOI]
  24. 24 AcrB Multidrug Efflux Pump of Escherichia coli : Composite Substrate-Binding Cavity of Exceptional Flexibility Generates Its Extremely Wide Substrate Specificity [DOI]
  25. 25 Applications of high-throughput ADME in drug discovery [DOI]
  26. 26 New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors [DOI]
  27. 27 Occurrence of Tetracycline Resistance Genes among Escherichia coli Isolates from the Phase 3 Clinical Trials for Tigecycline [DOI]
  28. 28 Therapeutic Applications of Quadruplex Nucleic Acids [DOI]
  29. 29 Prediction of Drug–Target Binding Kinetics by Comparative Binding Energy Analysis [DOI]
  30. 30 Physicochemical, Pharmaceutical, and Biological Considerations in GIT Absorption of Drugs [DOI]
  31. 31 TSAR, a new graph–theoretical approach to computational modeling of protein side‐chain flexibility: Modeling of ionization properties of proteins [DOI]
  32. 32 Design Principles for Quadruplex-binding Small Molecules [DOI]
  33. 33 Efflux pump-mediated antibiotics resistance: Insights from computational structural biology [DOI]
  34. 34 Glycosylation of Macrolide Antibiotics [DOI]
  35. 35 An Overview of Bacterial Efflux Pumps and Computational Approaches to Study Efflux Pump Inhibitors [DOI]
  36. 36 Prediction of Drug-Like Properties [DOI]
  37. 37 9.6 New Technologies for Molecular Dynamics Simulations [DOI]
  38. 38 Glycosylation of Antibiotics and Other Agents from Actinomycetes [DOI]
  39. 39 Indian Journal of Pharmaceutical Sciences [DOI]
  40. 40 Cryo-EM structure of multidrug efflux pump MexAB-OprM (0 degree state) [DOI]

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