ANTIBIOTICS POTENTIATORS AS AN ALTERNATIVE TO NEW ANTIBIOTICS: A REVIEW OF PROMISING APPROACHES

Antimicrobial resistance is a global problem in modern medicine, posing a threat to the effective prevention and treatment of an ever-increasing number of infections. One way to address this problem is to use substances that potentiate the action of previously inactive antibiotics. Potentiators represent an alternative to the development of new antibiotics. The purpose of the study. To study the potential use of substances that act as antibiotic potentiators and to evaluate the mechanisms of bacterial resistance to these substances.Materials and Methods. A systematic literature search was conducted in the international databases Google Scholar, PubMed, Scopus, Web of Science, and the Cochrane Library, covering publications from the past 5 years. Articles available in open access were included in the analysis, while preprints, duplicates, and overlapping publications were excluded. Inclusion criteria allowed peer-reviewed reviews and original research articles. The search for relevant publications was conducted using the keywords «antibiotic potentiator», «antibiotic adjuvant», and «antibiotic resistance». More than 1,000 articles were identified during the identification stage. Duplicate articles and publications not relevant to the study topic were excluded during screening, after which 117 articles were selected for analysis. At the final stage, 37 publications were included in the final review based on the inclusion and exclusion criteria. Results. Data analysis showed that the use of antibiotic potentiators can resuscitate resistant bacterial strains. The most promising potentiators are those that act as membrane permeabilizers, efflux pump inhibitors, and β-lactamase inhibitors.Conclusions. Antibiotic potentiators represent an innovative approach aimed at restoring the activity of existing drugs against resistant pathogens. However, the widespread clinical adoption of potentiators is fraught with challenges (toxicity, regulatory barriers, difficulty co-delivering with antibiotics, and potential for resistance to adjuvants). To overcome these barriers, further targeted research and support from the international community are needed. Antibiotic potentiators are not just a theoretical concept, but a real tool capable of winning time in the race against superbugs.

1. Uddin T.M., Chakraborty A.J., Ameer Khusro A., Zidan R.M., Mitra S., Emran T.B., Dhama K., Ripon K.H., Gajdács M., Sahibzada M.U., Hossain J., Koirala N. (2021). Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. Journal of Infection and Public Health, 14(12), 1750-1766. DOI: 10.1016/j.jiph.2021.10.020.

2. Urban-Chmiel R., Marek A., Stępień-Pyśniak D., Wieczorek K., Dec M., Nowaczek A., Osek J. (2022). Antibiotic Resistance in Bacteria-A Review. Antibiotics (Basel), 11(8), 1079. DOI: 10.3390/antibiotics11081079.

3. Nwobodo D.C., Eze P.M., Okezie U.M., Okafoanyali J.O., Okoye F.B., Esimone C.O. (2022). Bioactive compounds characterization and antimicrobial potentials of crude extract of Curvuiaria lunata, a fungal endophyte from Elaeis guneensis. Tropical Journal of Natural Product Research, 6(3), 395-402. DOI: 10.26538/tjnpr/v6i3.16.

4. Shree P., Singh C.K., Sodhi K.K., Surya J.N., Dileep Kumar Singh D.K. (2023). Biofilms: Understanding the structure and contribution towards bacterial resistance in antibiotics. Medicine in Microecology, 16, 100084. DOI: 10.1016/j.medmic.2023.100084.

5. Pinheiro F. (2024). Predicting the evolution of antibiotic resistance. Current Opinion in Microbiology, 82, 102542. DOI: 10.1016/j.mib.2024.102542.

6. Belay W.Y., Getachew M., Tegegne B.A., Teffera Z.H., Dagne A., Zeleke T.K., Abebe R.B., Gedif A.A., Fenta A., Yirdaw G., Tilahun A., Aschale Y. (2024). Mechanism of antibacterial resistance, strategies and next-generation antimicrobials to contain antimicrobial resistance: a review. Front Pharmacol, 15:1444781. DOI: 10.3389/fphar.2024.1444781.

7. Torrens G., Cava F. (2024). Mechanisms conferring bacterial cell wall variability and adaptivity. Biochemical Society Transactions, 52(5), 1981-1993. DOI: 10.1042/BST20230027.

8. Chawla M., Verma J., Gupta R., Das B. (2022). Antibiotic Potentiators Against Multidrug-Resistant Bacteria: Discovery, Development, and Clinical Relevance. Front Microbiol, 13, 887251. DOI: 10.3389/fmicb.2022.887251.

9. Paul D., Chawla M., Ahrodia T., Narendrakumar L., Das, B. (2023). Antibiotic Potentiation as a Promising Strategy to Combat Macrolide Resistance in Bacterial Pathogens. Antibiotics, 12(12), 1715. DOI: 10.3390/antibiotics12121715.

10. Boyd N.K., Teng C., Frei C.R. (2021). Brief Overview of Approaches and Challenges in New Antibiotic Development: A Focus On Drug Repurposing. Front Cell Infect Microbiol, 11, 684515. DOI: 10.3389/fcimb.2021.684515.

11. Bailey J., Gallagher L., Barker W.T., Hubble V.B., Gasper J., Melander C., Manoil C. (2022). Genetic Dissection of Antibiotic Adjuvant Activity. mBio, 13(1), e0308421. DOI: 10.1128/mbio.03084-21.

12. Kuang W., Zhang H., Wang X., Yang P. (2022). Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis. Acta Pharmaceutica Sinica B, 12(8), 3201-3214. DOI: 10.1016/j.apsb.2022.04.014.

13. Verma P., Tiwari M., Tiwari V. (2021). Efflux pumps in multidrug-resistant Acinetobacter baumannii: Current status and challenges in the discovery of efflux pumps inhibitors. Microbial Pathogenesis, 152, 104766. DOI: 10.1016/j.micpath.2021.104766.

14. Oncel B., Hasdemir U., Aksu B., Pournaras S. (2024). Antibiotic resistance in Campylobacter jejuni and Campylobacter coli: significant contribution of an RND type efflux pump in erythromycin resistance. Journal of Chemotherapy, 36(2), 110-118. DOI: 10.1080/1120009X.2023.2267895.

15. Zwama M., Nishino K. (2021). Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time. Antibiotics, 10(7), 774. DOI: 10.3390/antibiotics10070774.

16. Abbas A., Barkhouse A., Hackenberger D., Wright G.D. (2024). Antibiotic resistance: A key microbial survival mechanism that threatens public health. Cell Host & Microbe, 32(6), 837-851. DOI: 10.1016/j.chom.2024.05.015.

17. Gao Y., Chen H., Yang W., Wang S., Gong D., Zhang X., Huang Y., Kumar V., Huang Q., Kandegama W.M., Hao G. (2024). New avenues of combating antibiotic resistance by targeting cryptic pockets. Pharmacological Research, 210, 107495. DOI: 10.1016/j.phrs.2024.107495.

18. Ramirez D.M., Ramirez D., Arthur G., Zhanel G., Schweizer, F. (2022). Guanidinylated polymyxins as outer membrane permeabilizers capable of potentiating rifampicin, erythromycin, ceftazidime and aztreonam against gram-negative bacteria. Antibiotics, 11(10), 1277. DOI: 10.3390/antibiotics11101277.

19. Klobucar K., Brown E.D. (2022). New potentiators of ineffective antibiotics: targeting the gram-negative outer membrane to overcome intrinsic resistance. Current Opinion in Chemical Biology, 66, 102099. DOI: 10.1016/j.cbpa.2021.102099.

20. Pandey P., Sahoo R., Singh K., Pati S., Mathew J., Pandey A.C., Kant R., Han I., Choi E.H., Dwivedi G.R., Yadav D.K. (2021). Drug resistance reversal potential of nanoparticles/nanocomposites via antibiotic's potentiation in multi drug resistant P. aeruginosa. Nanomaterials (Basel), 12(1), 117. DOI: 10.3390/nano12010117.

21. Mubeen B., Ansar A.N., Rasool R., Ullah I., Imam S.S., Alshehri S., Ghoneim M.M., Alzarea S.I., Nadeem M.S., Kazmi I. (2021). Nanotechnology as a Novel Approach in Combating Microbes Providing an Alternative to Antibiotics. Antibiotics, 10(12), 1473. DOI: 10.3390/antibiotics10121473.

22. Silva N.B., Menezes R.P., Goncalves D.S., Santiago M.B., Conejo N.C., Souza S.L., Santos A.L., Silva R.S., Ramos S.B., Ferro E.A., Martins C.H. (2024). Exploring the antifungal, antibiofilm and antienzymatic potential of Rottlerin in an in vitro and in vivo approach. Scientific Reports, 14(1), 11132. DOI: 10.1038/s41598-024-61179-z.

23. Park C.H., Yang H., Kim S., Yun C.S., Jang B.C., Hong Y.J., Park D.S. (2024). Comparison of plasmid curing efficiency across five lactic acid bacterial species. Journal of Microbiology and Biotechnology, 34(11), 2385-2395. DOI: 10.4014/jmb.2406.06003.

24. Gao P., Wei Y., Tai S.S., Prakash P.H., Venicelu H.T., Li Y., Yam H.C., Chen J.H., Ho P.L., Davies J., Kao R.Y. (2022). Antivirulence agent as an adjuvant of β-lactam antibiotics in treating Staphylococcal infections. Antibiotics (Basel), 17(6), 819. DOI: 10.3390/antibiotics11060819.

25. Gil-Gil T., Laborda P., Martinez J.L., Hernando-Amado S. (2024). Use of adjuvants to improve antibiotic efficacy and reduce the burden of antimicrobial resistance. Expert review of anti-infective therapy, 23(1), 31-47. DOI: 10.1080/14787210.2024.2441891.

26. Ilin A.I., Kulmanov M.E., Korotetskiy I.S., Islamov R.A., Akhmetova G.K., Lankina M.V., Reva O.N. (2017). Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1. Frontiers of Cellular and Infection Microbiology, 7, 151. DOI: 10.3389/fcimb.2017.00151.

27. Ueoka K., Kabata T., Tokoro M., Kajino Y., Inoue D., Takagi T., Ohmori T., Yoshitani J., Ueno T., Yamamuro Y., Taninaka A., Tsuchiya H. (2021). Antibacterial Activity in Iodine-coated Implants Under Conditions of Iodine Loss: Study in a Rat Model Plus In Vitro Analysis. Clinical Orthopaedics and Related Research, 479(7), 1613-1623. DOI: 10.1097/CORR.0000000000001753.

28. Zhang Z., Weng B., Hu Z., Si Z., Li L., Yang Z., Cheng Y. (2024). Chitosan‑iodine complexes: Preparation, characterization, and antibacterial activity. International Journal of Biological Macromolecules, 260(2), 129598. DOI: 10.1016/j.ijbiomac.2024.129598.

29. Nevezhina A.V., Fadeeva T.V. (2023). Antimicrobial potential of iodine-containing substances and materials. ACTA Biomedica Scientifica, 8(5), 36-49. DOI: 10.29413/ABS.2023-8.5.4.

30. Reyes C., Patarroyo M.A. (2023). Adjuvants approved for human use: What do we know and what do we need to know for designing good adjuvants? European journal of pharmacology, 945, 175632. DOI: 10.1016/j.ejphar.2023.175632.

31. Butman H.S., Stefaniak M.A., Walsh D.J., Gondil V.S., Young M., Crow A.H., Nemeth A.M., Melander R.J., Dunman P.M., Melander C. (2025). Phenyl urea based adjuvants for β-lactam antibiotics against methicillin resistant Staphylococcus aureus. Bioorganic & Medicinal Chemistry Letters, 121, 130164. DOI: 10.1016/j.bmcl.2025.130164.

32. Pu Q., Wang Z., Li T., Li Q., Du M., Wang W., Yu Li Y. (2024). A novel in-silico strategy for the combined inhibition of intestinal bacterial resistance and the transfer of resistant genes using new fluoroquinolones, antibiotic adjuvants, and phytochemicals. Food Bioscience, 62, 105036. DOI: 10.1016/j.fbio.2024.105036.

33. Majdi С., Meffre P., Benfodda Z. (2024). Recent advances in the development of bacterial response regulators inhibitors as antibacterial and/or antibiotic adjuvant agent: A new approach to combat bacterial resistance. Bioorganic Chemistry, 150, 107606. DOI: 10.1016/j.bioorg.2024.107606.

34. Panjla A., Kaul G., Shukla M., Akhir A., Tripathi S., Arora A., Chopra S., Sandeep Verma S. (2024). Membrane-targeting, ultrashort lipopeptide acts as an antibiotic adjuvant and sensitizes MDR gram-negative pathogens toward narrow-spectrum antibiotics. Biomedicine & Pharmacotherapy, 176, 116810. DOI: 10.1016/j.biopha.2024.116810.

35. Dey R., Mukherjee S., Mukherjee R., Haldar J. (2023). Small molecular adjuvants repurpose antibiotics towards Gram-negative bacterial infections and multispecies bacterial biofilms. Chemical Science, 15(1), 259-270. DOI: 10.1039/d3sc05124b.