Antibacterial Efficacy of Linezolid Alone and in Combination with Zinc Oxide Nanoparticles against Methicillin-Resistant S. Aureus Clinical Isolates

ORIGINAL ARTICLE
Imran Khan, Sara Ali, Ikram Khan, Salma Mohamed, Sarmir Khan, Feroz Khan, Hassan Higazi

 
International Journal of Biomedicine. 2022;12(3):454-458.
DOI: 10.21103/Article12(3)_OA20
Originally published September 5, 2022

Abstract: 

Skin and soft tissue infections caused by methicillin-resistant S. aureus (MRSA) are among the most common bacterial infections. Linezolid is a cortisone drug for the treatment of infections caused by MRSA. However, developing resistance to linezolid creates a hurdle in the treatment of these infections. The present study aimed to determine the activity of linezolid alone and in combination with zinc oxide nanoparticles (ZnO-NPs) for the purpose of reducing resistance and enhancing its efficacy. For this study, MRSA isolates were taken and confirmed by using the antibiotic susceptibility testing method. The minimum inhibitory concentration (MIC) of both antibiotics and nanoparticles against MRSA clinical isolates was done by using the broth microdilution method. A checkerboard assay has used the determination of the combined activity of linezolid and ZnO-NPs. ZnO-NPs displayed a spherical shape with smooth surface morphology and had a mean size of 10 nm to 20 nm, with a zeta potential of 3.57 mV. The activity of ZnO-NPs against MRSA clinical isolates was 200 µg/ml. Almost 81% of isolates were found sensitive to linezolid with MIC lower than 4 µg/ml, and 19% were resistant, having MIC greater than 4 µg/ml. The combination of an antibiotic and nanoparticles reduced the activity of each of them twofold. The current study revealed that both linezolid and ZnO-NPs have antimicrobial activity against MRSA when used alone. The combination of both medications reduces each other's MIC twofold and has an antagonistic impact. Further research is needed to determine the mechanism through which these medications inhibit each other's activity.

Keywords: 
nanoparticles • linezolid • zinc oxide • S. aureus • tissue infections
References: 
  1. Yang S, Han X, Yang Y, Qiao H, Yu Z, Liu Y, et al. Bacteria-Targeting Nanoparticles with Microenvironment-Responsive Antibiotic Release To Eliminate Intracellular Staphylococcus aureus and Associated Infection. ACS Appl Mater Interfaces. 2018 May 2;10(17):14299-14311. doi: 10.1021/acsami.7b15678. Epub 2018 Apr 19. PMID: 29633833.
  2. Aung MS, San T, Urushibara N, San N, Hlaing MS, Soe PE, et al. Clonal Diversity and Molecular Characteristics of Methicillin-Susceptible and -Resistant Staphylococcus aureus from Pediatric Patients in Myanmar. Microb Drug Resist. 2022 Feb;28(2):191-198. doi: 10.1089/mdr.2021.0051. Epub 2021 Oct 6. PMID: 34619061.
  3. Tabaja H, Hindy JR, Kanj SS. Epidemiology of Methicillin-Resistant Staphylococcus Aureus in Arab Countries of the Middle East and North African (MENA) Region. Mediterr J Hematol Infect Dis. 2021 Sep 1;13(1):e2021050. doi: 10.4084/MJHID.2021.050. PMID: 34527202; PMCID: PMC8425352.
  4. Assar NH. Emergence of resistance to last-resort antibiotics in clinical isolates of staphylococci with special reference to daptomycin and linezolid. Egypt J Med Microbiol. 2021;30:191–199.
  5. Burgin DJ, Liu R, Hsieh RC, Heinzinger LR, Otto M. Investigational agents for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: progress in clinical trials. Expert Opin Investig Drugs. 2022 Mar;31(3):263-279. doi: 10.1080/13543784.2022.2040015. Epub 2022 Feb 14. PMID: 35129409.
  6. Usachev KS, Yusupov MM, Validov SZ. Hibernation as a Stage of Ribosome Functioning. Biochemistry (Mosc). 2020 Nov;85(11):1434-1442. doi: 10.1134/S0006297920110115. PMID: 33280583.
  7. Shariati A, Dadashi M, Chegini Z, van Belkum A, Mirzaii M, Khoramrooz SS, Darban-Sarokhalil D. The global prevalence of Daptomycin, Tigecycline, Quinupristin/Dalfopristin, and Linezolid-resistant Staphylococcus aureus and coagulase-negative staphylococci strains: a systematic review and meta-analysis. Antimicrob Resist Infect Control. 2020 Apr 22;9(1):56. doi: 10.1186/s13756-020-00714-9. PMID: 32321574; PMCID: PMC7178749.
  8. Zhao H, Brooks SA, Eszterhas S, Heim S, Li L, Xiong YQ, et al. Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing. Sci Adv. 2020 Sep 2;6(36):eabb9011. doi: 10.1126/sciadv.abb9011. PMID: 32917596; PMCID: PMC7467700.
  9. Ghosh C, Sarkar P, Issa R, Haldar J. Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance. Trends Microbiol. 2019 Apr;27(4):323-338. doi: 10.1016/j.tim.2018.12.010. Epub 2019 Jan 22. PMID: 30683453.
  10. Awad M. Pharmaceutical studies on Egyptian kaolins for healthcare uses.2018. Available at: https://dialnet.unirioja.es/servlet/tesis?codigo=148490
  11. Souza VGL, Rodrigues C, Valente S, Pimenta C, Pires JRA, Alves MM, et al. Eco-friendly ZnO/Chitosan bionanocomposites films for packaging of fresh poultry meat. Coatings.2020; 10(2): 110. https://doi.org/10.3390/coatings10020110
  12. Rudramurthy GR, Swamy MK, Sinniah UR, Ghasemzadeh A. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes. Molecules. 2016 Jun 27;21(7):836. doi: 10.3390/molecules21070836. PMID: 27355939; PMCID: PMC6273897.
  13. Qiu S, Zhou H, Shen Z, Hao L, Chen H, Zhou X. Synthesis, characterization, and comparison of antibacterial effects and elucidating the mechanism of ZnO, CuO and CuZnO nanoparticles supported on mesoporous silica SBA-3. RSC Adv. 2020 Jan 15;10(5):2767-2785. doi: 10.1039/c9ra09829a. PMID: 35496109; PMCID: PMC9048980.
  14. Naqvi QU, Kanwal A, Qaseem S, Naeem M, Ali SR, Shaffique M, Maqbool M. Size-dependent inhibition of bacterial growth by chemically engineered spherical ZnO nanoparticles. J Biol Phys. 2019 Jun;45(2):147-159. doi: 10.1007/s10867-019-9520-4. Epub 2019 Feb 5. PMID: 30721424; PMCID: PMC6548786.
  15. Ukkund SJ, Ashraf M, Udupa AB, Gangadharan M, Pattiyeri A, Marigowda YK, et al. Synthesis and characterization of silver nanoparticles from Fuzarium Oxysporum and investigation of their antibacterial activity. Mater. Today: Proc. 2019;9:506–514.
  16. Shaikh S, Nazam N, Rizvi SMD, Ahmad K, Baig MH, Lee EJ, Choi I. Mechanistic Insights into the Antimicrobial Actions of Metallic Nanoparticles and Their Implications for Multidrug Resistance. Int J Mol Sci. 2019 May 18;20(10):2468. doi: 10.3390/ijms20102468. PMID: 31109079; PMCID: PMC6566786.
  17. Rai MK, Deshmukh SD, Ingle AP, Gade AK. Silver nanoparticles: the powerful nanoweapon against multidrug-resistant bacteria. J Appl Microbiol. 2012 May;112(5):841-52. doi: 10.1111/j.1365-2672.2012.05253.x. Epub 2012 Mar 28. PMID: 22324439.
  18. Vazquez-Muñoz R, Meza-Villezcas A, Fournier PGJ, Soria-Castro E, Juarez-Moreno K, Gallego-Hernández AL, et al. Enhancement of antibiotics antimicrobial activity due to the silver nanoparticles impact on the cell membrane. PLoS One. 2019 Nov 8;14(11):e0224904. doi: 10.1371/journal.pone.0224904. PMID: 31703098; PMCID: PMC6839893.
  19. Liao F, Gu W, Fu X, Yuan B, Zhang Y. Community-acquired methicillin-resistant Staphylococcus aureus provoked cytokine storm causing severe infection on BALB/c mice. Mol Immunol. 2021 Dec;140:167-174. doi: 10.1016/j.molimm.2021.10.013. Epub 2021 Oct 28. PMID: 34717146.
  20. Hoang TPN, Ghori MU, Conway BR. Topical Antiseptic Formulations for Skin and Soft Tissue Infections. Pharmaceutics. 2021 Apr 15;13(4):558. doi: 10.3390/pharmaceutics13040558. PMID: 33921124; PMCID: PMC8071503.
  21. Church NA, McKillip JL. Antibiotic resistance crisis: Challenges and imperatives. Biologia (Bratisl).2021;76:1535–1550.
  22. Ghosh S, Lahiri D, Nag M, Dey A, Pandit S, Sarkar T, et al. Phytocompound Mediated Blockage of Quorum Sensing Cascade in ESKAPE Pathogens. Antibiotics (Basel). 2022 Jan 5;11(1):61. doi: 10.3390/antibiotics11010061. PMID: 35052938; PMCID: PMC8773049.
  23. Kihara R, Nagata Y, Kiyoi H, Kato T, Yamamoto E, Suzuki K, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014 Aug;28(8):1586-95. doi: 10.1038/leu.2014.55. Epub 2014 Feb 3. PMID: 24487413.
  24. Carvalhaes CG, Sader HS, Shortridge D, Streit JM, Mendes RE. 1369. Oritavancin Activity Against Methicillin-Resistant S. aureus (MRSA) Isolates Causing Skin and Skin Structure Infections in US Hospitals (2017-2019). Open Forum Infectious Diseases. 2021;8(Issue Supplement_1):S770–S771.
  25. Bashir Ahmad B, Khan F, Ahmed J, Cha SB, Shin MK, Bashir S, Yoo HS. Antibiotic Resistance Pattern and Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus Colonization in Burns Unit of a Tertiary Care Hospital in Peshawar, Pakistan.Tropical Journal of Pharmaceutical Research. December 2014;3(12):2091-2099
  26. Koskei LC. In Vitro Studies of the Effects of Purple Tea (Camellia Sinensis) Extracts on Selected Human Cancer Cell Lines and Multi-drug Resistant Bacteria. University of Nairobi.2019. http://erepository.uonbi.ac.ke/handle/11295/152829
  27. Jesline A, John NP, Narayanan PM, Vani C, Murugan S. Antimicrobial activity of zinc and titanium dioxide nanoparticles against biofilm-producing methicillin-resistant Staphylococcus aureus. Appl Nanosci. 2015;5:157–162.
  28. Aleaghil SA, Fattahy E, Baei B, Saghali M, Bagheri H, Javid N, et al. Antibacterial activity of zinc oxide nanoparticles on Staphylococcus aureus. Int J Adv Biotechnol Res.2016; 7:1569–1575.
  29. Panáček A, Smékalová M, Kilianová M, Prucek R, Bogdanová K, Večeřová R, et al. Strong and Nonspecific Synergistic Antibacterial Efficiency of Antibiotics Combined with Silver Nanoparticles at Very Low Concentrations Showing No Cytotoxic Effect. Molecules. 2015 Dec 28;21(1):E26. doi: 10.3390/molecules21010026. PMID: 26729075; PMCID: PMC6273824.
  30. Jelinkova P, Mazumdar A, Sur VP, Kociova S, Dolezelikova K, Jimenez AMJ, et al. Nanoparticle-drug conjugates treating bacterial infections. J Control Release. 2019 Aug 10;307:166-185. doi: 10.1016/j.jconrel.2019.06.013. Epub 2019 Jun 19. PMID: 31226356.
  31. Möhler JS, Sim W, Blaskovich MAT, Cooper MA, Ziora ZM. Silver bullets: A new lustre on an old antimicrobial agent. Biotechnol Adv. 2018 Sep-Oct;36(5):1391-1411. doi: 10.1016/j.biotechadv.2018.05.004. Epub 2018 May 27. PMID: 29847770.
  32. Smekalova M, Aragon V, Panacek A, Prucek R, Zboril R, Kvitek L. Enhanced antibacterial effect of antibiotics in combination with silver nanoparticles against animal pathogens. Vet J. 2016 Mar;209:174-9. doi: 10.1016/j.tvjl.2015.10.032. Epub 2015 Oct 22. PMID: 26832810.

Download Article
Received June 11, 2022.
Accepted July 22, 2022.
©2022 International Medical Research and Development Corporation.