Antibacterial Activity of Exogenous Glutathione and Its Synergism on Antibiotics in Methicillin-Associated Multidrug Resistant Clinical Isolates of <i>Staphylococcus aureus</i> — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
Antibacterial Activity of Exogenous Glutathione and Its Synergism on Antibiotics in Methicillin-Associated Multidrug Resistant Clinical Isolates of <i>Staphylococcus aureus</i>
Department of Biology, Long Island University, Brooklyn, NY, USA
,
Department of Biology, Long Island University, Brooklyn, NY, USA
,
Department of Biology, Long Island University, Brooklyn, NY, USA
1 Department of Biology, Long Island University, Brooklyn, NY, USA
2 Department of Biology, Long Island University, Brooklyn, NY, USA
3 Department of Biology, Long Island University, Brooklyn, NY, USA
Background: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most problematic human pathogens. Antibiotic treatment of MRSA often associated with resistance to multiple classes of antibiotics is extremely challenging and urgently demands action to treat MRSA. Glutathione (GSH) is a biogenic thiol-compound that maintains an optimal intracellular redox-potential required for various normal cellular processes. Antibacterial activity of exogenous GSH has been reported in some bacterial pathogens but is largely unknown in MRSA. Aim: This study aimed to understand antibacterial activity of GSH, its role in antibiotic susceptibility, and a potential antibacterial mechanism in clinical isolates of S. aureus . Materials and Methods: Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), checkerboard, time-killing, and bacterial killing assays were performed for 14 clinical isolates of S. aureus including 10 MRSA and two type strains (ATCC 700699 and 35556). Results: MIC and MBC levels for the clinical and type strains were 15 - 20 mM and 25 - 40 mM of GSH, respectively. Subinhibitory concentrations of GSH synergistically enhanced susceptibility of all tested-antibiotics, resulting in sensitizing all-tested S. aureus . Bacterial-killing produced by GSH-mediated acidity was significantly higher than that by hydrochloric acid-mediated acidity. Conclusion: Overall results concluded that GSH exhibited antibacterial activity on S. aureus regardless of antibiotic susceptibility and synergistically enhanced antibiotic susceptibility. Additionally, GSH-mediated acidity was one of the antibacterial mechanisms. These findings suggest that GSH may be a potential antimicrobial agent or adjuvant for the conventional anti-MRSA regimens.
Turner, N.A., Sharma-Kuinkel, B.K., Maskarinec, S.A., et al. (2019) Methicillin-Resistant Staphylococcus aureus: An Overview of Basic and Clinical Research. Nature Reviews Microbiology, 17, 203-218. https://doi.org/10.1038/s41579-018-0147-4
Brown, N.M., Goodman, A.L., Horner, C., Jenkins, A. and Brown, E.M. (2021) Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA): Updated Guidelines from the UK. JAC-Antimicrobal Resistance, 3, dlaa114. https://doi.org/10.1093/jacamr/dlaa114
Barrett, F.F., McGehee, R.F. and Finland, M. (1968) Methicillin-Resistant Staphylococcus aureus at Boston City Hospital. Bacteriologic and Epidemiologic Observations. The New England Journal of Medicine, 279, 441-448. https://doi.org/10.1056/NEJM196808292790901
Lakhundi, S. and Zhang, K. (2018) Methicillin-Resistant Staphylococcus aureus: Molecular Characterization, Evolution, and Epidemiology. Clinical Microbiology Reviews, 31, e00020-18. https://doi.org/10.1128/CMR.00020-18
Styers, D., Sheehan, D.J., Hogan, P. and Sahm, D.F. (2006) Laboratory-Based Surveillance of Current Antimicrobial Resistance Patterns and Trends among Staphylococcus aureus: 2005 Status in the United States. Annals of Clinical Microbiology and Antimicrobials, 5, Article No. 2. https://doi.org/10.1186/1476-0711-5-2
Chambers, H.F. and Deleo, F.R. (2009) Waves of Resistance: Staphylococcus aureus in the Antibiotic Era. Nature Reviews Microbiology, 7, 629-641. https://doi.org/10.1038/nrmicro2200
Malachowa, N. and DeLeo, F.R. (2010) Mobile Genetic Elements of Staphylococcus aureus. Cellular and Molecular Life Sciences, 67, 3057-3071. https://doi.org/10.1007/s00018-010-0389-4
Chen, C.J., Huang, Y.C. and Chiu, C.H. (2015) Multiple Pathways of Cross-Resistance to Glycopeptides and Daptomycin in Persistent MRSA Bacteraemia. Journal of Antimicrobial Chemotherapy, 70, 2965-2972. https://doi.org/10.1093/jac/dkv225
Weigel, L.M., Clewell, D.B., Gill, S.R., et al. (2003) Genetic Analysis of a High-Level Vancomycin-Resistant Isolate of Staphylococcus aureus. Science, 302, 1569-1571. https://doi.org/10.1126/science.1090956
Ruiz-Ripa, L., Fessler, A.T., Hanke, D., et al. (2021) Mechanisms of Linezolid Resistance among Clinical Staphylococcus spp. in Spain: Spread of Methicillin- and Linezolid-Resistant S. epidermidis ST2. Microbial Drug Resistance, 27, 145-153. https://doi.org/10.1089/mdr.2020.0122
Varela, M.C., Roch, M., Taglialegna, A., et al. (2020) Carbapenems Drive the Collateral Resistance to Ceftaroline in Cystic Fibrosis Patients with MRSA. Communications Biology, 3, Article No. 599. https://doi.org/10.1038/s42003-020-01313-5
Bongiorno, D., Mongelli, G., Stefani, S. and Campanile, F. (2019) Genotypic Analysis of Italian MRSA Strains Exhibiting Low-Level Ceftaroline and Ceftobiprole Resistance. Diagnostic Microbiology and Infectious Disease, 95, Article ID: 114852. https://doi.org/10.1016/j.diagmicrobio.2019.06.004
Antimicrobial Resistance C (2022) Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis. The Lancet, 399, 629-655.
Smirnova, G.V. and Oktyabrsky, O.N. (2005) Glutathione in Bacteria. Biochemistry Biokhimiia, 70, 1199-1211. https://doi.org/10.1007/s10541-005-0248-3
Huang, C.S., Moore, W.R. and Meister, A. (1988) On the Active Site Thiol of Gamma-Glutamylcysteine Synthetase: Relationships to Catalysis, Inhibition, and Regulation. Proceedings of the National Academy of Sciences of the United States of America, 85, 2464-2468. https://doi.org/10.1073/pnas.85.8.2464
Yamaguchi, H., Kato, H., Hata, Y., et al. (1993) Three-Dimensional Structure of the Glutathione Synthetase from Escherichia coli B at 2.0 A Resolution. Journal of Molecular Biology, 229, 1083-1100. https://doi.org/10.1006/jmbi.1993.1106
Fahey, R.C., Brown, W.C., Adams, W.B. and Worsham, M.B. (1978) Occurrence of Glutathione in Bacteria. Journal of Bacteriology, 133, 1126-1129. https://doi.org/10.1128/jb.133.3.1126-1129.1978
Smirnova, G.V., Muzyka, N.G., Glukhovchenko, M.N. and Oktyabrsky, O.N. (2000) Effects of Menadione and Hydrogen Peroxide on Glutathione Status in Growing Escherichia coli. Free Radical Biology & Medicine, 28, 1009-1016. https://doi.org/10.1016/S0891-5849(99)00256-7
Helmann, J.D. (2011) Bacillithiol, a New Player in Bacterial Redox Homeostasis. Antioxidants & Redox Signaling, 15, 123-133. https://doi.org/10.1089/ars.2010.3562
Masip, L., Veeravalli, K. and Georgiou, G. (2006) The Many Faces of Glutathione in Bacteria. Antioxidants & Redox Signaling, 8, 753-762. https://doi.org/10.1089/ars.2006.8.753
Schairer, D.O., Chouake, J.S., Kutner, A.J., et al. (2013) Evaluation of the Antibiotic Properties of Glutathione. Journal of Drugs in Dermatology, 12, 1272-1277.
Zhang, Y. and Duan, K. (2009) Glutathione Exhibits Antibacterial Activity and Increases Tetracycline Efficacy against Pseudomonas aeruginosa. Science China Life Sciences, 52, 501-505. https://doi.org/10.1007/s11427-009-0074-8
Paez, P.L., Becerra, M.C. and Albesa, I. (2010) Effect of the Association of Reduced Glutathione and Ciprofloxacin on the Antimicrobial Activity in Staphylococcus aureus. FEMS Microbiology Letters, 303, 101-105. https://doi.org/10.1111/j.1574-6968.2009.01867.x
Smirnova, G., Muzyka, N., Lepekhina, E. and Oktyabrsky, O. (2016) Roles of the Glutathione- and Thioredoxin-Dependent Systems in the Escherichia coli Responses to Ciprofloxacin and Ampicillin. Archives of Microbiology, 198, 913-921. https://doi.org/10.1007/s00203-016-1247-z
Kwon, D.H., Hekmaty, S. and Seecoomar, G. (2013) Homeostasis of Glutathione Is Associated with Polyamine-Mediated Beta-Lactam Susceptibility in Acinetobacter baumannii ATCC 19606. Antimicrobial Agents and Chemotherapy, 57, 5457-5461. https://doi.org/10.1128/AAC.00692-13
Alharbe, R., Almansour, A. and Kwon, D.H. (2017) Antibacterial Activity of Exogenous Glutathione and Its Synergism on Antibiotics Sensitize Carbapenem-Associated Multidrug Resistant Clinical Isolates of Acinetobacter baumannii. International Journal of Medical Microbiology, 307, 409-414. https://doi.org/10.1016/j.ijmm.2017.07.009
Kwon, D.H. and Lu, C.D. (2007) Polyamine Effects on Antibiotic Susceptibility in Bacteria. Antimicrobial Agents and Chemotherapy, 51, 2070-2077. https://doi.org/10.1128/AAC.01472-06
Kanagaratnam, R., Sheikh, R., Alharbi, F. and Kwon, D.H. (2017) An Efflux Pump (MexAB-OprM) of Pseudomonas aeruginosa Is Associated with Antibacterial Activity of Epigallocatechin-3-Gallate (EGCG). Phytomedicine, 36, 194-200. https://doi.org/10.1016/j.phymed.2017.10.010
White, R.L., Burgess, D.S., Manduru, M. and Bosso, J.A. (1996) Comparison of Three Different in Vitro Methods of Detecting Synergy: Time-Kill, Checkerboard, and E Test. Antimicrobial Agents and Chemotherapy, 40, 1914-1918. https://doi.org/10.1128/AAC.40.8.1914
Das, T., Paino, D., Manoharan, A., et al. (2019) Conditions under Which Glutathione Disrupts the Biofilms and Improves Antibiotic Efficacy of both ESKAPE and Non-ESKAPE Species. Frontiers in Microbiology, 10, Article No. 2000. https://doi.org/10.3389/fmicb.2019.02000