Inhibitory effect of Atorvastatin on the secretion of extracellular virulence products by Methicillin resistant Staphylococcus aureus

Fraidoon Abdulqader Salih

doi:10.21271/ZJPAS.33.4.8

Authors

Fraidoon Abdulqader Salih Deparemrnt of Biology, College of Science, Salahaddin University – Erbil, Kurdistan Region, Iraq.

DOI:

https://doi.org/10.21271/ZJPAS.33.4.8

Keywords:

MRSA, Atorvastatin, Haemolysin, α-Toxin.

Abstract

Statins are lipid-lowering therapeutic agents that have displayed useful anti-inflammatory and antibacterial properties. The focus of this research study was to understand the role of statins in controlling bacterial pathogenicity. Haemolysins and some other substances secreted by S. aureus were inhibited by Atorvastatin. It was found that Atorvastatin had a negligible effect on the growth of the bacteria at subminimal inhibitory concentrations, meanwhile it significantly reduced the secretion of haemolysins, coagulase and catalase. Thus, Atorvastatin could be used in conjunction with some antibiotics in controlling Methicillin resistant S. aureus MRSA infections and immunomodulation of the defense system.

References

Adhikari, R.P., Novick, R.P., 2005. Subinhibitory cerulenin inhibits staphylococcal exoprotein production by blocking transcription rather than by blocking secretion. Microbiology, 151, 3059–3069. https://doi.org/10.1099/mic.0.28102-0

Altenbern, R.A., 1977. Extreme Sensitivity of Staphylococcal Enterotoxin B and C Production to Inhibition by Cerulenin. Antimicrob. Agents Chemother. 11, 906–908. https://doi.org/10.1128/AAC.11.5.906

Berkeley, R.C.W., Pepper, E.A., Caulfield, M.P., Melling, J., 1987. The inhibition of Staphylococcus aureus enterotoxin a production by cerulenin and quinacrine; presumptive evidence for a lipid intermediate/protease release mechanism. FEMS Microbiol. Lett. 40, 103–105. https://doi.org/10.1111/j.1574-6968.1987.tb02010.x

Castiglione, V., Chiriacò, M., Emdin, M., Taddei, S., Vergaro, G., 2020. Statin therapy in COVID-19 infection. Eur. Heart J. — Cardiovasc. Pharmacother. https://doi.org/10.1093/ehjcvp/pvaa042

Caulfield, M.P., Berkeley, R.C., Pepper, E.A., Melling, J., 1979. Export of extracellular levansucrase by Bacillus subtilis: inhibition by cerulenin and quinacrine. J. Bacteriol. 138, 345–351.

Cauz, A.C.G., Carretero, G.P.B., Saraiva, G.K.V., Park, P., Mortara, L., Cuccovia, I.M., Brocchi, M., Gueiros-Filho, F.J., 2019. Violacein Targets the Cytoplasmic Membrane of Bacteria. ACS Infect. Dis. 5, 539–549. https://doi.org/10.1021/acsinfecdis.8b00245

Chung, P.Y., 2020. Novel targets of pentacyclic triterpenoids in Staphylococcus aureus: A systematic review. Phytomedicine 73, 152933. https://doi.org/10.1016/j.phymed.2019.152933

Ciaravino, V., Kropko, M.L., Rothwell, C.E., Hovey, C.A., Theiss, J.C., 1995. The genotoxicity profile of atorvastatin, a new drug in the treatment of hypercholesterolemia. Mutat. Res. Toxicol. 343, 95–107. https://doi.org/10.1016/0165-1218(95)90076-4

DeMars, Z., Singh, V.K., Bose, J.L., 2020. Exogenous Fatty Acids Remodel Staphylococcus aureus Lipid Composition through Fatty Acid Kinase. J. Bacteriol. 202. https://doi.org/10.1128/JB.00128-20

Engels, W., Kamps, M.A.F., 1981. Secretion of staphylocoagulase by Staphylococcus aureus: the role of a cell-bound intermediate. Antonie Van Leeuwenhoek 47, 509–524. https://doi.org/10.1007/BF00443238

Fishman, Y., Rottem, S., Citri, N., 1978. Evidence linking penicillinase formation and secretion to lipid metabolism in Bacillus licheniformis. J. Bacteriol. 134, 434–439.

Graziano, T.S., Cuzzullin, M.C., Franco, G.C., Schwartz-Filho, H.O., Andrade, E.D. de, Groppo, F.C., Cogo-Müller, K., 2015. Statins and Antimicrobial Effects: Simvastatin as a Potential Drug against Staphylococcus aureus Biofilm. PLOS ONE 10, e0128098. https://doi.org/10.1371/journal.pone.0128098

Guerin Maryse, Lassel Taous S., Le Goff Wilfried, Farnier Michel, Chapman M. John, 2000. Action of Atorvastatin in Combined Hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 20, 189–197. https://doi.org/10.1161/01.ATV.20.1.189

Hennessy, E., Adams, C., Reen, F.J., O’Gara, F., 2016. Is There Potential for Repurposing Statins as Novel Antimicrobials? Antimicrob. Agents Chemother. 60, 5111–5121. https://doi.org/10.1128/AAC.00192-16

Hiltunen, M., Söderhäll, K., 1992. Inhibition of polyketide synthesis in Alternaria alternata by the fatty acid synthesis inhibitor cerulenin. Appl. Environ. Microbiol. 58, 1043–1045.

Hirano, T., Murakami, M., 2020. COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome. Immunity 52, 731–733. https://doi.org/10.1016/j.immuni.2020.04.003

Horn, M.P., Knecht, S.M., Rushing, F.L., Birdsong, J., Siddall, C.P., Johnson, C.M., Abraham, T.N., Brown, A., Volk, C.B., Gammon, K., Bishop, D.L., McKillip, J.L., McDowell, S.A., 2008. Simvastatin Inhibits Staphylococcus aureus Host Cell Invasion through Modulation of Isoprenoid Intermediates. J. Pharmacol. Exp. Ther. 326, 135–143. https://doi.org/10.1124/jpet.108.137927

Jacques, N.A., 1983. Membrane Perturbation by Cerulenin Modulates Glucosyltransferase Secretion and Acetate Uptake by Streptococcus salivarius. Microbiology, 129, 3293–3302. https://doi.org/10.1099/00221287-129-11-3293

Khan, A., Wilson, B., Gould, I.M., 2018. Current and future treatment options for community-associated MRSA infection. Expert Opin. Pharmacother. 19, 457–470. https://doi.org/10.1080/14656566.2018.1442826

Khan, T.J., Ahmed, Y.M., Zamzami, M.A., Mohamed, S.A., Khan, I., Baothman, O.A.S., Mehanna, M.G., Yasir, M., 2018. Effect of atorvastatin on the gut microbiota of high fat diet-induced hypercholesterolemic rats. Sci. Rep. 8, 662. https://doi.org/10.1038/s41598-017-19013-2

Ko, H.H.T., Lareu, R.R., Dix, B.R., Hughes, J.D., 2017. Statins: antimicrobial resistance breakers or makers? PeerJ 5, e3952. https://doi.org/10.7717/peerj.3952

Lakhundi, S., Zhang, K., 2018. Methicillin-Resistant Staphylococcus aureus: Molecular Characterization, Evolution, and Epidemiology. Clin. Microbiol. Rev. 31. https://doi.org/10.1128/CMR.00020-18

Liu, C.-I., Liu, G.Y., Song, Y., Yin, F., Hensler, M.E., Jeng, W.-Y., Nizet, V., Wang, A.H.-J., Oldfield, E., 2008. A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence. Science 319, 1391–1394. https://doi.org/10.1126/science.1153018

Liu, G.Y., Essex, A., Buchanan, J.T., Datta, V., Hoffman, H.M., Bastian, J.F., Fierer, J., Nizet, V., 2005. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202, 209–215. https://doi.org/10.1084/jem.20050846

Manalo, R.V.M., Josol, V.J.D., Gloriani, N.G., 2017. The differential effects of atorvastatin co-administered with ampicillin on the bacterial growth and biofilm formation of Staphylococcus aureus. Curr. Med. Res. Pract. 7, 178–183. https://doi.org/10.1016/j.cmrp.2017.08.002

MÄntsälä, P., 1982. Inhibition of Protein Secretion by Cerulenin in Bacillus subtilis. Microbiology, 128, 2967–2972. https://doi.org/10.1099/00221287-128-12-2967

Naimi, T.S., 2003. Comparison of Community- and Health Care–Associated Methicillin-Resistant Staphylococcus aureus Infection. JAMA 290, 2976. https://doi.org/10.1001/jama.290.22.2976

PATON, J.C., MAY, B.K., ELLIOTT, W.H., 1980. Cerulenin Inhibits Production of Extracellular Proteins but not Membrane Proteins in Bacillus amyloliquefaciens. Microbiology, 118, 179–187. https://doi.org/10.1099/00221287-118-1-179

Petit‐Glatron, M.-F., Chambert, R., 1981. Levansucrase of Bacillus subtilis: Conclusive Evidence that Its Production and Export are Unrelated to Fatty-Acid Synthesis but Modulated by membrane-Modifying Agents. Eur. J. Biochem. 119, 603–611. https://doi.org/10.1111/j.1432-1033.1981.tb05650.x

Price, A.C., Choi, K.-H., Heath, R.J., Li, Z., White, S.W., Rock, C.O., 2001. Inhibition of β-Ketoacyl-Acyl Carrier Protein Synthases by Thiolactomycin and Cerulenin STRUCTURE AND MECHANISM. J. Biol. Chem. 276, 6551–6559. https://doi.org/10.1074/jbc.M007101200

Pruefer Diethard, Scalia Rosario, Lefer Allan M., 1999. Simvastatin Inhibits Leukocyte–Endothelial Cell Interactions and Protects Against Inflammatory Processes in Normocholesterolemic Rats. Arterioscler. Thromb. Vasc. Biol. 19, 2894–2900. https://doi.org/10.1161/01.ATV.19.12.2894

Ragia, G., Manolopoulos, V.G., 2020. Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies. Eur. J. Clin. Pharmacol. 1–8. https://doi.org/10.1007/s00228-020-02963-4

Rana, R., Sharma, R., Kumar, A., 2019. Repurposing of Existing Statin Drugs for Treatment of Microbial Infections: How Much Promising? Infect. Disord. - Drug TargetsDisorders 19, 224–237. https://doi.org/10.2174/1871526518666180806123230

Saleh, F.A.K., Freer, J.H., 1984. Inhibition of Secretion of Staphylococcal Alph Toxin by Cerulenin. J. Med. Microbiol. 18, 205–216. https://doi.org/10.1099/00222615-18-2-205

Sarkeshikian, S.S., Ghadir, M.R., Alemi, F., Jalali, S.M., Hormati, A., Mohammadbeigi, A., 2020. Atorvastatin in combination with conventional antimicrobial treatment of Helicobacter pylori eradication: A randomized controlled clinical trial. J. Gastroenterol. Hepatol. 35, 71–75. https://doi.org/10.1111/jgh.14810

Siddiqui, A.H., Koirala, J., 2020. Methicillin Resistant Staphylococcus Aureus, in: StatPearls. StatPearls Publishing, Treasure Island (FL).

Silhavy, T.J., Benson, S.A., Emr, S.D., 1983. Mechanisms of protein localization. Microbiol. Rev. 47, 313–344.

Wang, J., Ye, X., Yang, X., Cai, Y., Wang, S., Tang, J., Sachdeva, M., Qian, Y., Hu, W., Leeds, J.A., Yuan, Y., 2020. Discovery of Novel Antibiotics as Covalent Inhibitors of Fatty Acid Synthesis. ACS Chem. Biol. 15, 1826–1834. https://doi.org/10.1021/acschembio.9b00982

Welsh, A.-M., Kruger, P., Faoagali, J., 2009. Antimicrobial action of atorvastatin and rosuvastatin. Pathology (Phila.) 41, 689–691. https://doi.org/10.3109/00313020903305860

Zhang, X.-J., Qin, J.-J., Cheng, X., Shen, L., Zhao, Y.-C., Yuan, Y., Lei, F., Chen, M.-M., Yang, H., Bai, L., Song, X., Lin, L., Xia, M., Zhou, F., Zhou, J., She, Z.-G., Zhu, L., Ma, X., Xu, Q., Ye, P., Chen, G., Liu, L., Mao, W., Yan, Y., Xiao, B., Lu, Z., Peng, G., Liu, M., Yang, Jun, Yang, L., Zhang, C., Lu, H., Xia, X., Wang, D., Liao, X., Wei, X., Zhang, B.-H., Zhang, X., Yang, Juan, Zhao, G.-N., Zhang, P., Liu, P.P., Loomba, R., Ji, Y.-X., Xia, J., Wang, Y., Cai, J., Guo, J., Li, H., 2020. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 32, 176-187.e4. https://doi.org/10.1016/j.cmet.2020.06.015