IS MRSA REVERSIBLE? DOES E-POLYLYSINE HOLD PROMISE AS AN ADJUVANT DRUG TO TREAT METHICILLIN RESISTANT S. AUREUS?

SIREESHA DIVYAKOLU¹, VENKATARAMAN SRITHARAN²*
¹Global Medical Education and Research Foundation & Molecular Diagnostics and Biomarkers Laboratory, Gleneagles Global Hospitals, Hyderabad, 500004, Telangana, India; Centre for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technolog
²Department of Molecular Diagnostics & Biomarkers, Global Medical Education & Research Foundation (GMERF), Gleneagles Global Hospitals, Hyderabad, 500 004, Telangana, India
* Corresponding Author : venkataraman.sritharan@gmail.com

Received : 01-01-2023     Accepted : 27-01-2023     Published : 30-01-2023
Volume : 15     Issue : 1       Pages : 2001 - 2004
Int J Microbiol Res 15.1 (2023):2001-2004

Keywords : Adjuvant drug, mecA, MRSA, MSSA, E-Poly Lysine
Academic Editor : Dr Mudit Chandra, Reddypriya Pasupuleti, Dr Ranjana Hawaldar, V. C. Ingle
Conflict of Interest : None declared
Acknowledgements/Funding : Authors are thankful to Global Medical Education and Research Foundation & Molecular Diagnostics and Biomarkers Laboratory, Gleneagles Global Hospitals, Lakdi-ka-pul, Hyderabad, 500 004, Telangana, India. Authors are also thankful to Dr Ranganathan Iyer , Department of Microbiology, Gleneagles Global Hospital for providing the clinical isolates and National Institute of Nutrition, Hyderabad, 500007 for assistance of SEM studies
Author Contribution : All authors equally contributed

The present study was aimed to investigate if ?-Poly Lysine (? PL) has the potential to be repurposed for treating MRSA. Poly Lysine (? PL) was tested for anti MRSA activity by disc diffusion assay against 5-100 µg/ml and the Minimal Inhibitory Concentration was determined by the broth micro dilution method. The disc diffusion assay was also used to do preliminary screen of ? PL to know its antimicrobial activity. All experiments were performed at sub-MIC of ? PL so that the bacteria do not come under stress (microbicidal effect). The mecA genotype was confirmed by PCR after every passage and the reversibility of MRSA phenotype was investigated after successive passages on agar plates by disc diffusion against Cefoxitin and Oxacillin. The morphological changes were observed under SEM. The MICs of ? PL was 12.5 µg/ml and 20 µg/ml for MSSA and MRSA isolates respectively by disc diffusion method. However, the MICs determined by broth micro dilution method were 6.25 µg/ml for both MSSA and MRSA isolates. The anti-MRSA activity of ? PL is inducible in the bacteria. After four passages, the Cefoxitin inhibition zone increased from 0 mm to 18 mm. mecA could be detected in cells of all passages. The cells started collapsing after the first passage and appeared elongated with indentations, lysed, distorted and membrane severely disrupted with increasing passages. ?- PL inhibited the growth of MSSA and MRSA. It also reversed MRSA phenotype and restored sensitivity of the bacteria to methicillin. It appears to act through an independent mechanism. ? PL could be re-purposed to treat MRSA and also used in co-therapy to avoid development of drug resistance

1. Lowy F.D. (1998) New England Journal of Medicine, 339(8), 520-532.
2. Lim D. and Strynadka N.C.J. (2002) Nature Structural Biology, 9(11), 870-876.
3. Temime L., Boëlle P.Y., Courvalin P., and Guillemot D. (2003) Emerging Infectious Diseases, 9(4), 411-417.
4. Upadhyay H.C. (2021) Current Topics in Medicinal Chemistry, 21(8), 737-752.
5. McCusker M.P., Alves Ferreira D., Cooney D., Martins Alves B., Fanning S., Pagès J.M., Martins M. and Davin-Regli A. (2019) Journal of Global Antimicrobial Resistance, 16, 187-198.
6. Mahlapuu M., Håkansson J., Ringstad L. and Björn C. (2016) Frontiers in Cellular and Infection Microbiology, 6, 194.
7. Melander R.J. and Melander C. (2017) ACS Infect Dis., 3, 559-563.
8. Laws M., Shaaban A. and Rahman K.M. (2019) FEMS Microbiology Reviews, 43(5), 490-516.
9. Wright G.D. (2016) Trends in Microbiology, 24(11), 928.
10. Hiraki J., Ichikawa T., Ninomiya S., Seki H., Uohama K., Seki H., Kimura S., Yanagimoto Y. and Barnett J.W.Jr. (2003) Regulatory Toxicology and Pharmacology: RTP, 37(2), 328-340.
11. Yoshida T. and Nagasawa T. (2003) Applied Microbiology and Biotechnology, 62(1), 21-26.
12. Fürsatz M., Skog M., Sivlér P., Palm E., Aronsson, C., Skallberg A. and Aili D. (2018) Biomedical Materials (Bristol, England), 13(2), 025014.
13. Jiang S., Zeng M., Zhao Y., Wu H. and Zhang F. (2019) International Journal of Biological Macromolecules, 127, 349-356.
14. Badaoui Najjar M., Kashtanov D. and Chikindas M.L. (2007) Letters in Applied Microbiology, 45(1), 13-18.
15. Hyldgaard M., Mygind T., Vad B. S., Stenvang M., Otzen D.E. and Meyer R.L. (2014) Applied and Environmental Microbiology, 80(24), 7758-7770.
16. Cleveland J., Montville T.J., Nes I.F. and Chikindas M.L. (2001) International Journal of Food Microbiology, 71(1), 1-20
17. Babic M., Horák D., Trchová M., Jendelová P., Glogarová K., Lesný, P. and Syková, E. (2008) Bioconjugate Chemistry, 19(3), 740-750.
18. Zhang X., Oulad-Abdelghani M., Zelkin AN., Wang Y., Haîkel Y., Mainard D., Voegel J.C., Caruso F. and Benkirane-Jessel N. (2010) Biomaterials, 31(7), 1699-170.
19. Shukla S. C., Singh A., Pandey A.K. and Mishra A. (2012) Biochemical Engineering Journal, 65, 70-78.
20. Wang L., Zhang C., Zhang J., Rao Z., Xu X., Mao Z., and Chen X. (2021) Frontiers in Bioengineering and Biotechnology, 9, 748976.
21. Akgul C. and Saglikoglu G. (2005) Indian Journal of Biochemistry & Biophysics, 42(6), 395-397.
22. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals. (n.d.). In CLSI standard VET01. Wayne, PA.
23. Tan Z., Shi Y., Xing B., Hou Y., Cui J. and Jia S. (2019) Bioresour. Bioprocess, 6.
24. Stegger M., Andersen P. S., Kearns A., Pichon B., Holmes M. A., Edwards G., Laurent F., Teale C., Skov R. and Larsen A. R. (2012) Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, 18(4), 395-400.
25. Kong C., Chee C.F., Richter K., Thomas N., Abd. Rahman N. and Nathan S. (2018) Scientific Reports, 8(1).
26. Mendelson M. and Matsoso M.P. (2015) South African Medical Journal, 105(5), 325.
27. Willyard C. (2017) Nature, 543(7643), 15.
28. Venter H. (2019) Bioscience Reports, 39(4), BSR20180474.
29. Jain S., Sengupta M., Sarkar S., Ghosh S., Mitra A. N., Sinha A. and Chakravorty S. (2016) Journal of Clinical and Diagnostic Research: JCDR, 10(2), DC22-5.
30. Martin JK 2nd, Sheehan J.P., Bratton B.P., Moore G.M., Mateus A., Li SH., Kim H., Rabinowitz J.D., Typas A., Savitski M.M., Wilson M.Z. and Gitai Z. A (2020) Cell, 181(7), 1518-1532.e14.
31. Munita J. M. and Arias C. A. (2016) Microbiology Spectrum, 4(2).
32. Chusri S., Villanueva I., Voravuthikunchai, S. P. and Davies J. (2009) The Journal of Antimicrobial Chemotherapy, 64(6), 1203-1211.
33. Karumathil D. P., Nair M. S., Gaffney J., Kollanoor-Johny A., and Venkitanarayanan K. (2018) Frontiers in Microbiology, 9.
34. Zhang X., Shi C., Liu Z., Pan F., Meng R., Bu X., Xing H., Deng Y., Guo N and Yu L. (2018) J. of Medical Microbiology, 67(6), 838-845.
35. Wu Q.X., Wang Z.D., Zheng M.F., Su T., Wang X.H., Guan Y.X., and Chen Y. (2020) International Journal of Biological Macromolecules, 155, 411-420.
36. Chen S., Huang S., Li Y. and Zhou C. (2021) Frontiers in Chemistry, 9, 659304.