High Concentrations of Sodium Chloride Improve Microbicidal Activity of Ibuprofen against Common Cystic Fibrosis Pathogens
Adrián J Muñoz, Roxana V Alasino, Ariel G Garro, Valeria Heredia, Néstor H García, David C Cremonezzi, Dante M Beltramo, Adrián J Muñoz, Roxana V Alasino, Ariel G Garro, Valeria Heredia, Néstor H García, David C Cremonezzi, Dante M Beltramo
Abstract
Ibuprofen (IBU-H), a widely used anti-inflammatory, also shows a marked antimicrobial effect against several bacterial species, including those involved in cystic fibrosis such as Pseudomona aeruginosa, methicillin resistant Staphylococcus aureus and Burkholderia cepacia complex. Additionally, our results show significant synergy between water soluble Na-ibuprofen (IBU-Na) and ionic strength. Salt concentrations above 0.5 M modify the zeta potential promoting the action of Na-IBU; thus, with 1 M sodium chloride, IBU-Na is ten times more efficient than in the absence of ionic strength, and the minimum effective contact time is reduced from hours to minutes. In short time periods, where neither IBU-Na nor controls with 1 M NaCl show activity, the combination of both leads to a reduction in the bacterial load. We also analyzed whether the changes caused by salt on the bacterial membrane also promoted the activity of other microbicide compounds used in cystic fibrosis like gentamicin, tobramycin and phosphomycin. The results show that the presence of ionic strength only enhanced the bactericidal activity of the amphipathic molecule of IBU-Na. In this respect, the effect of saline concentration was also reflected in the surface properties of IBU-Na, where, in addition to the clear differences observed between 145 mM and 1 M, singular behaviors were also found, different in each condition. The combination of anti-inflammatory activity and this improved bactericidal effect of Na-IBU in hypertonic solution provides a new alternative for the treatment of respiratory infections of fibrotic patients based on known and widely used compounds.
Keywords: P. aeruginosa; bactericide activity; cystic fibrosis; ibuprofen; synergy.
Conflict of interest statement
The authors declare no conflict of interest.
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References
- Cantas L., Shah Q.A., Cavaco L.M., Manaia C.M., Walsh F., Popowska M., Garelick H., Bürgmann H., Sørum H. A brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiota. Front. Microbiol. 2014;4:96. doi: 10.3389/fmicb.2013.00096.
- Davies J., Wright G.D. Bacterial resistance to aminoglycoside antibiotics. Trends Microbiol. 1997;5:234–240. doi: 10.1016/S0966-842X(97)01033-0.
- Higgins C.F. Multiple molecular mechanisms for multidrug resistance transporters. Nature. 2007;446:749–757. doi: 10.1038/nature05630.
- Hooper D.C. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin. Infect. Dis. 2000;31:24–28. doi: 10.1086/314056.
- Nikaido H. Multidrug Resistance in Bacteria. Annu. Rev. Biochem. 2009;78:119–146. doi: 10.1146/annurev.biochem.78.082907.145923.
- Poole K. Aminoglycoside Resistance in Pseudomona aeruginosa. Antimicrob. Agents Chemother. 2005;49:479–487. doi: 10.1128/AAC.49.2.479-487.2005.
- Livermore D.M. The need for new antibiotics. Clin. Microbiol. Infect. 2004;10:1–9. doi: 10.1111/j.1465-0691.2004.1004.x.
- Barrett C.T., Barrett J.F. Antibacterials: Are the new entries enough to deal with the emerging resistance problems? Curr. Opin. Biotechnol. 2003;14:621–626. doi: 10.1016/j.copbio.2003.10.003.
- Cole S.T. Who will develop new antibacterial agents? Philos. Trans. R. Soc. Lond. B Biol. Sci. 2014;369 doi: 10.1098/rstb.2013.0430.
- Conly J.M., Johnston B.L. Where are all the new antibiotics? The new antibiotic paradox. Can. J. Infect. Dis. Med. Microbiol. 2005;16:159–160. doi: 10.1155/2005/892058.
- Franco B.E., Martínez M.A., Sánchez Rodríguez M.A., Wertheimer A.I. The determinants of the antibiotic resistance process. Infect. Drug Resist. 2009;2:1–11.
- Kruszewska H., Zar Ba T., Tyski S. Examination of antimicrobial activity of selected Non-antibiotic medicinal preparations. Acta Pol. Pharm. Drug Res. 2012;69:1368–1371.
- Obad J., Suskovic J., Kos B. Antimicrobial activity of ibuprofen: New perspectives on an ‘‘Old’’ non-antibiotic drug. Eur. J. Pharm. Sci. 2015;71:93–98. doi: 10.1016/j.ejps.2015.02.011.
- Elvers K.T., Wright S.J. Antibacterial activity of the anti-inflammatory compound ibuprofen. Lett. Appl. Microbiol. 1995;20:82–84. doi: 10.1111/j.1472-765X.1995.tb01291.x.
- Mohsen A., Gomaa A., Mohamed F., Ragab R., Eid M., Ahmed A., Khalaf A., Kamal M., Mokhtar S., Mohamed H., et al. Antibacterial, Anti-biofilm Activity of Some Non-steroidal Anti-Inflammatory Drugs and N-acetyl Cysteine against Some Biofilm Producing Uropathogens. Am. J. Epidemiol. Infect. Dis. 2015;3:1–9. doi: 10.12691/ajeid-3-1-1.
- Hersh E.V., Hammond B.F., Fleury A.A. Antimicrobial activity of flurbiprofen and ibuprofen in vitro against six common periodontal pathogens. J. Clin. Dent. 1991;3:1–5.
- Sanyal A.K., Roy D., Chowdhury B., Banerjee A.B. Ibuprofen, a unique anti-inflammatory compound with antifungal activity against dermatophytes. Lett. Appl. Microbiol. 1993;17:109–111. doi: 10.1111/j.1472-765X.1993.tb01436.x.
- Donaldson S.H., Bennett W.D., Zeman K.L., Knowles M.R., Tarran R., Boucher R.C. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N. Engl. J. Med. 2006;354:241–250. doi: 10.1056/NEJMoa043891.
- Robinson M., Regnis J.A., Bailey D.L., King M., Bautovich G.J., Bye P.T. Effect of hypertonic saline, amiloride, and cough on mucociliary clearance in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 1996;153:1503–1509. doi: 10.1164/ajrccm.153.5.8630593.
- Wark P., McDonald V.M. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst. Rev. 2009;2:CD001506. doi: 10.1002/14651858.CD001506.pub3.
- Clinical and Laboratory Standards Institute . Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 9th ed. Clinical and Laboratory Standards Institute; Wayne, PA, USA: 2012. Approved Standard; CLSI document M07-A9.
- AWWA/WEF . Standard Methods for the Examination of Water and Wastewater. 21st ed. AWWA/WEF; Denver, CO, USA: 2005. Part 9215.
- Halder S., Yadav K.K., Sarkar R., Mukherjee S., Saha P., Haldar S., Karmakar S., Sen T. Alteration of Zeta potential and membrane permeability in bacteria: A study with cationic agents. SpringerPlus. 2015;4:672. doi: 10.1186/s40064-015-1476-7.
- Pillet F., Formosa-Dague C., Baaziz H., Dague E., Rols M. Cell wall as a target for bacteria inactivation by pulsed electric fields. Sci. Rep. 2016;6:19778. doi: 10.1038/srep19778.
- Rao S., Grigg J. New insights into pulmonary inflammation in cystic fibrosis. Arch. Dis. Child. 2006;91:786–788. doi: 10.1136/adc.2004.069419.
- Corvol H., Fitting C., Shadelat K., Jacquo T., Tabari O., Boul M. Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 2003;284:997–1003. doi: 10.1152/ajplung.00156.2002.
- Konstan M.W. Ibuprofen therapy for cystic fibrosis lung disease: Revisited. Curr. Opin. Pulm. Med. 2008;14:567–573. doi: 10.1097/MCP.0b013e32831311e8.
- Konstan M.W., Byard P.J., Hoppel C.L., Davis P.B. Effect of high-dose ibuprofen in patients with cystic fibrosis. N. Engl. J. Med. 1995;332:848–854. doi: 10.1056/NEJM199503303321303.
- Konstan M.W., Krenicky J.E., Finney M.R., Kirchner H.L., Hilliard K.A., Hilliard J.B., Davis P.B., Hoppel C.L. Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis. J. Pharmacol. Exp. Ther. 2003;306:1086–1091. doi: 10.1124/jpet.103.052449.
- Konstan M.W., Vargo K.M., Davis P.B. Ibuprofen Attenuates the Inflammatory Response to Pseudomonas aeruginosa in a Rat Model of Chronic Pulmonary Infection. Am. Rev. Respir. Dis. 1990;141:186–192. doi: 10.1164/ajrccm/141.1.186.
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