Generic placeholder image

Anti-Infective Agents


ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

Review Article

Pharmacological Exploitation of Non-Steroidal Anti-inflammatory Drugs as Potential Sources of Novel Antibacterial Agents

Author(s): Ebrahim M. Yimer*, Ousman A. Mohammed and Seid I. Mohammedseid

Volume 17, Issue 2, 2019

Page: [81 - 92] Pages: 12

DOI: 10.2174/2211352516666181008114542


The ever-increasing threat of bacterial infections and antimicrobial resistance calls for a global effort to deal with this problem. This fast and universal dissemination of antimicrobialresistant bacterial strains resulted in the diminution of therapeutic alternatives for various infectious diseases. Besides, the unaffordability of efficacious antimicrobials coupled with the occurrence of unpleasant adverse effects calls for the exploration of alternative agents with possible antibacterial effect. All these challenges of microbes have posed new drives to the scientific communities. Researchers are now assessing the possible alternative antimicrobial agents for fighting bacterial infections and antimicrobial resistance. Therefore, this review emphasizes on the role of nonsteroidal anti-inflammatory agents as potential sources of novel antibacterial agents on which preliminary studies and randomized controlled trials had been performed. The review also deals with the possible antibacterial mechanism of actions and the likely effects of non-steroidal antiinflammatory drugs when combined along with conventional antibacterial agents.

Keywords: Antibacterial agent, non-steroidal anti-inflammatory drugs, antibiotic resistance, minimum inhibitory concentration, bacterial infections, non-antibiotic compounds.

Graphical Abstract
Nii-Trebi, N.I. Emerging and neglected infectious diseases: Insights, advances, and challenges Review. BioMed Res. Int., 2017, 52, 450-421.
World Health Organization (WHO)-The top 10 causes of death 2016. (Accessed on 19 July 2017).
Moges, F.; Endris, M.; Mulu, A. The growing challenges of antibacterial drug resistance in Ethiopia. J. Glob. Antimicrob. Resist., 2014, 2, 148-154.
Michalopoulos, A.; Falagas, M.E. Colistin and polymyxin B in critical care. Crit. Care Clin., 2008, 24(2), 377-391.
Mesfin, T. Some medicinal plants of central Shewa and Southwestern Ethiopia. Sinet Ethiop. J. Sci., 1986, 9, 143-168.
Nakka, M.; Nallapati, S.B.; Reddy, L.V.; Murakkant, K.; Pal, S. Synthesis characterization and anti-bacterial screening of piroxicam-based sulfonates. J. Chem. Pharm. Res., 2011, 3, 581-588.
Yin, Z.; Wang, Y.; Whittell, L.; Jergic, S.; Liu, M.; Harry, E.; Dixon, N.E.; Kelso, M.J.; Beck, J.L.; Oakley, A.J. DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs. Chem. Biol., 2014, 21, 481-487.
Annaduri, S.; Basu, S.; Ray, S.; Dastidar, S.G.; Chakrabarty, A.N. Antimicrobial activity of the antiinflammatory agent, diclofenac sodium. Indian J. Exp. Biol., 2008, 36, 86-90.
Kristiansen, J.E. The antimicrobial activity of non-antibiotics. Report from a congress on the antimicrobial effect of drugs other than antibiotics on bacteria, viruses, protozoa, and other organisms. A.P.M.I.S. Suppl., 1992, 30, 7-14.
Williams, J.D. The Garrod lecture. Selective toxicity and concordant pharmacodynamics of antibiotics and other drugs. J. Antimicrob. Chemother., 1995, 35, 721-737.
Kristiansen, J.E.; Amaral, L. The potential management of resistant infections with nonantibiotics. J. Antimicrob. Chemother., 1997, 40, 319-327.
Himber, J.; Andermann, G.; Erhart, M.; Leclerc, G.; Bouzoubaa, M. In vitro potential measurement, anaesthetic and antimicrobial effects as indicators of beta-blocker toxicity of the cornea. Methods Find. Exp. Clin. Pharmacol., 1985, 7, 195-201.
Giunta, S.; Galeazzi, L.; Turchetti, G.; Sampaoli, G.; Groppa, G. Effect of amiloride on the intracellular sodium and potassium content of intact Streptococcus faecalis cells in vitro. Antimicrob. Agents Chemother., 1986, 29, 958-969.
Gerber, H.R.; Anton, A.H. A bacterial model for the evaluation of barbiturates. Arch. Int. Pharmacodyn. Ther., 1974, 212, 284-296.
Cederlund, H.; Mardh, P.A. Antibacterial activities of non-antibiotic drugs. J. Antimicrob. Chemother., 1993, 32, 355-365.
Iwahi, T.; Satoh, H.; Nakao, M.; Iwasaki, T.; Yamazaki, T.; Kubo, K.; Tamura, T.; Imada, A. Lansoprazole, a novel benzimidazole proton pump inhibitor, and its related compounds have selective activity against Helicobacter pylori. Antimicrob. Agents Chemother., 1991, 35, 90-96.
Parry, M.F.; Neu, H.C. Effect of N-acetylcysteine on antibiotic activity and bacterial growth in vitro. J. Clin. Microbiol., 1977, 5, 58-61.
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.
Ahmed, E.F.; Abd El-Baky, R.M.; Ahmed, A.F.; Fawzy, N.G.; Aziz, N.A.; Gad, G.F.M. Evaluation of antibacterial activity of some non-steroidal anti-inflammatory drugs against bacteria causing urinary tract infection. Afr. J. Microbiol., 2017, 10(34), 1408-1416.
Munoz-Criado, S.; Munoz-Bellido, J. GarciaRodriguez, J. In vitro activity of nonsteroidal anti-inflammatory agents, phenothiazines and antidepressants against Brucella species. Eur. J. Clin. Microbiol. Infect. Dis., 1996, 15, 418-420.
Pina-Vaz, C.; Rodrigues, A.G.; Costa-de-Oliveira, S.; Ricardo, E.; Mårdh, P.A. Potent synergic effect between ibuprofen and azoles on Candida resulting from blockade of efflux pumps as determined by FUN-1 staining and flow cytometry. J. Antimicrob. Chemother., 2005, 56(4), 678-685.
Al-Janabi, A.A.H. In vitro antibacterial activity of ibuprofen and acetaminophen. J. Glob. Infect. Dis., 2010, 2(2), 105-108.
Chan, E.W.L.; Yee, Z.W.; Raja, I.; Yap, J.K.Y. Synergistic effect of non-steroidal anti-inflammatory drugs (NSAIDs) on antibacterial activity of cefuroxime and chloramphenicol against methicillin-resistant S. aureus. J. Glob. Antimicrob. Resist., 2017, 10, 70-74.
Al-kuraishy, H.M.; Algareeb, A.I.; Al-windy, S.A. Experimental antibacterial activity of selective cyclooxygenase antagonist. Int. J. Basic Clin. Pharmacol., 2013, 2(4), 381-385.
Zimmermann, P.; Curtis, N. Antimicrobial effects of antipyretics. Antimicrob. Agents Chemother., 2017, 61(4), e02268-e02316.
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.
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.
Chowdhury, B.; Adak, M.; Bose, S.K. Flurbiprofen, a unique nonsteroidal anti-inflammatory drug with antimicrobial activity against Trichophyton, Microsporum and Epidermophyton species. Lett. Appl. Microbiol., 2003, 37, 158-161.
Wang, W.H.; Wong, W.M.; Dailidiene, D.; Breg, D.E.; Gu, Q.; Lai, K.C. Aspirin inhibits the growth of Helicobacter pylori and enhances its susceptibility to antimicrobial agents. Gut, 2003, 52, 490-495.
Hasan, M.S.; Das, N. A detailed in vitro study of naproxen metal complexes in quest of new therapeutic possibilities. Alexandria. J. Medic., 2017, 53, 157-165.
Rossolini, G.M.; Mantengoli, E.; Docquier, J.; Musmanno, R.; Coratza, G. Epidemiology of infections caused by multiresistant Gram-negatives: ESBLs, MBLs, pan-resistant strains. New Microbiol., 2007, 30, 332-339.
Cavalieri, S.J.; Harbeck, R.J.; McCarter, Y.S.; Ortez, I.; Rankin, J.H.; Sautter, R.L. Manual of antimicrobial susceptibility testing: antimicrobial resistance among Staphylococci; University of Washington: Washington, 2005, pp. 101-102.
Tepes, B.; O’Connor, A.; Gisbert, J.; O’Morain, C. Treatment of Helicobacter pylori infection. Helicobacter, 2012, 17(1), 36-42.
Akhter, T.; Baqai, R.; Aziz, M. Antibacterial effect of NSAIDs on clinical isolates of urinary tract infection and diabetic foot infection. Pak. J. Pharm. Sci., 2010, 23(1), 108-113.
Podpletnya, O.A.; Khomiak, O.V.; Koshova, I.P. NSAIDs: Can the presence of infectious agent influence the choice of analgesic drug? Pathologia, 2017, 14(2), 219-223.
Ture, Z.; Demiraslan, H.; Kontas, O.; Alp, E.; Doganay, M. The Role of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) intramuscular injection in the development and severity of deep soft tissue infection in mice. Fundam. Clin. Pharmacol., 2017.
Jiang, C.; Geng, J.; Hu, H.; Ma, H.; Gao, X.; Ren, H. Impact of selected non-steroidal anti-inflammatory pharmaceuticals on microbial community assembly and activity in sequencing batch reactors. PLoS One, 2017, 12(6)e0179236
Shah, P.N.; Marshall-Batty, K.R.; Smolen, J.A.; Tagaev, J.A.; Chen, Q.; Rodesney, C.A.; Le, H.H.; Gordon, V.D.; Greenberg, D.E.; Cannon, C.L. Antimicrobial activity of ibuprofen against cystic fibrosis associated gram-negative pathogens. Antimicrob. Agents Chemother., 2018, 62(3), e01574-e01617.
Kronenberg, A.; Bütikofer, L.; Odutayo, A.; Mühlemann, K.; da Costa, B.; Battaglia, M.; Meli, D.N.; Frey, P.; Limacher, A.; Rechenbach, S.; Jüni, P. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: Randomised, double blind trial. BMJ, 2017, 359, j4784.
Bleidorn, J.; Gágyor, I.; Kochen, M.M.; Wegscheider, K.; Hummers-Pradier, E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? - Results of a randomized controlled pilot trial. BMC Med., 2010, 8, 30.
Davis, J.S.; Mackrow, C.; Binks, P.; Fletcher, W.; Dettwiller, P.; Marshall, C.; Day, J.; Pratt, W.; Tong, S.Y. A double-blind randomised controlled trial of ibuprofen compared with placebo for uncomplicated cellulitis of the upper or lower limb. Clin. Microbiol. Infect., 2017.
Gágyor, I.; Bleidorn, J.; Kochen, M.M.; Schmiemann, G.; Wegscheider, K.; Hummers-Pradier, E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: Randomised controlled trial. BMJ, 2015, 351, h6544.
Farha, M.; Leung, A.A.; Sewell, E.W.; D’Elia, M.; Allison, S.E.; Ejim, L.; Pereira, P.M.; Pinho, M.G.; Wright, G.D.; Brown, E.D. Inhibition of WTA synthesis blocks the cooperative active of PBPs and sensitizes MRSA to β-lactams. ACS Chem. Biol., 2013, 8(1), 226-233.
Zhou, A.; Kang, T.M.; Yuan, J.; Beppler, C.; Nguyen, C.; Mao, Z.; Nguyen, M.Q.; Yeh, P.; Miller, J.H. Synergistic interactions of vancomycin with different antibiotics against Escherichia coli: trimethoprim and nitrofurantoin display strong synergies with vancomycin against wild-type E. coli. Antimicrob. Agents Chemother., 2015, 59(1), 276-281.
del Prado, G. Marti’Nez-Mari’N, C.; Huelves, L.; Gracia, M.; Rodri’Guez-Cerrato, V.; Ferna’Ndez-Roblas, R.; Ponte, C.; Cenjor, C.; Soriano, F. Impact of Ibuprofen therapy in the outcome of experimental pneumococcal acute otitis media treated with amoxicillin or erythromycin. Pediatr. Res., 2006, 60(5), 555-559.
Singh, R.; Chaudhary, R.K.; Dumka, V.K. Influence of paracetamol on the pharmacokinetics and dosage regimen of ceftizoxime in cross bred calves. Isra. J. Veterin. Med., 2008, 63, 72-76.
Byrne, S.T.; Denkin, S.M.; Zhang, Y. Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis. J. Antimicrob. Chemother., 2007, 59, 313-316.
Kupferwasser, L.I.; Yeaman, M.R.; Shapiro, S.M.; Nast, C.C.; Sullam, P.M.; Filler, S.G. Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental S. aureus endocarditis through antiplatelet and antibacterial effects. Circulation, 1999, 99, 2791-2797.
Gu, Q.; Xia, H.H.; Wang, W.H.; Wang, J.D.; Wong, W.M.; Chan, A.O.; Yuen, M.F.; Lam, S.K.; Cheung, H.K.; Liu, X.G.; Wong, B.C. Effect of cyclo-oxygenase inhibitors on Helicobacter pylori susceptibility to metronidazole and clarithromycin. Aliment. Pharmacol. Ther., 2004, 20(6), 675-681.
Pina-Vaz, C.; Sansonetty, F.; Rodrigues, A.G.; Martinez-De-Oliveira, J.; Fonseca, A.F.; Mardh, P.A. Antifungal activity of ibuprofen alone and in combination with fluconazole against Candida species. J. Med. Microbiol., 2000, 49, 831-840.
Tyski, S. Non-antibiotics-drugs with additional antimicrobial activity. Acta Pol. Pharm., 2010, 60, 401-404.
Lee, C.H.; Su, L.H.; Liu, J.W.; Chang, C.C.; Chen, R.F.; Yang, K.D. Aspirin enhances opsono-phagocytosis and is associated to a lower risk for Klebsiella pneumoniae invasive syndrome. BMC Infect. Dis., 2014, 14, 47.
Kang, G.; Balasubramanian, K.A.; Koshi, A.R.; Mathan, M.M.; Mathan, V.I. Salicylate inhibits fimbriae mediated HEp-2 cell adherence of and haemagglutination by enteroaggregative Escherichia coli. FEMS Microbiol. Lett., 1998, 166, 257-265.
Kunin, C.M.; Hua, T.H.; Guerrant, R.L.; Bakaletz, L.O. Effect of salicylate, bismuth, osmolytes, and tetracycline resistance on expression of fimbriae by Escherichia coli. Infect. Immun., 1994, 62, 2178-2186.
Kunin, C.M.; Hua, T.H.; Bakaletz, L.O. Effect of salicylate on expression of flagella by Escherichia coli and Proteus, Providencia, and Pseudomonas spp. Infect. Immun., 1995, 63, 1796-1799.
Repaske, D.R.; Adler, J. Change in intracellular pH of Escherichia coli mediates the chemotactic response to certain attractants and repellents. J. Bacteriol., 1981, 145, 1196-1208.
Farber, B.F.; Wolff, A.G. The use of nonsteroidal anti-inflammatory drugs to prevent adherence of Staphylococcus epidermidis to medical polymers. J. Infect. Dis., 1992, 166, 861-865.
Ashraf, A.; Yousri, F.; Taha, N.; El-Waly, O.A. E-K, A. Ramadan.; E. Ismail. Effect of some non-steroidal anti-inflammatory drugs on growth, adherence and mature biofilms of Candida spp. Afr. J. Microbiol. Res., 2015, 3, 1-7.
Muller, E.; Al-Attar, J.; Wolff, A.G.; Farber, B.F. Mechanism of salicylate mediated inhibition of biofilm in Staphylococcus epidermidis. J. Infect. Dis., 1998, 177, 501-503.
Vila, J.; Soto, S.M. Salicylate increases the expression of marA and reduces in vitro biofilm formation in uropathogenic Escherichia coli by decreasing type 1 fimbriae expression. Virulence, 2012, 3, 280-285.
Carvalho, A.P.; Gursky, L.C.; Rosa, R.T.; Rymovicz, A.U.; Campelo, P.M.; Gregio, A.M. Non-steroidal anti-inflammatory drugs may modulate the protease activity of Candida albicans. Microb. Pathog., 2010, 49, 315-322.
El-Mowafy, S.A.; Abd El Galil, K.H.; El-Messery, S.M.; Shaaban, M.I. Aspirin is an efficient inhibitor of quorum sensing, virulence and toxins in Pseudomonas aeruginosa. Microb. Pathog., 2014, 74, 25-32.
Prithiviraj, B.; Bais, H.P.; Weir, T.; Suresh, B.; Najarro, E.H.; Dayakar, B.V. Down regulation of virulence factors of Pseudomonas aeruginosa by salicylic acid attenuates its virulence on Arabidopsis thaliana and Caenorhabditis elegans. Infect. Immun., 2005, 73, 5319-5328.
Drago, L.; De Vecchi, E.; Nicola, L.; Valli, M.; Gismondo, M.R. Effects of subinhibitory concentrations of ibuprofen iso-buthanol ammonium on virulence factors of uropathogenic Escherichia coli. J. Chemother., 2002, 14, 314-315.
Stevens, D. Could nonsteroidal anti-inflammatory drugs (NSAIDs) enhance the progression of bacterial infections to toxic shock syndrome? Clin. Infect. Dis., 2009, 21, 977-980.
Madigan, M.; Martinko, J.; Parter, J. Microbial growth control. In: Brock TD (ed.), Brock biology of microorganisms. 9th ed. Prentice HillInc, USAS. 2000.
Schonthal, A. Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy. Br. J. Cancer, 2009, 97(11), 1465-1468.
Dutta, N.K.; Mazumdar, K.; Baek, M.W.; Kim, D.J.; Na, Y.R.; Park, S.H.; Lee, H.K.; Lee, B.H.; Park, J.H. In vitro efficacy of diclofenac against Listeria monocytogenes. Eur. J. Clin. Microbiol. Infect. Dis., 2008, 27, 315-319.
Mazumdar, K.; Dutta, N.K.; Dastidar, S.G.; Motohashi, N.; Shirataki, Y. Diclofenac in the management of E. coli urinary tract infections. In Vivo, 2006, 20, 613-620.
Mai, N.T.H.; Dobbs, N.; Phu, N.H.; Colas, R.A.; Thao, L.T.B.; Thuong, N.T.T.; Nghia, H.D.T.; Hanh, N.H.H.; Hang, N.T.; Heemskerk, A.D.; Day, J.N.; Ly, L.; Thu, D.D.; Merson, L.; Kestelyn, E.; Wolbers, M.; Geskus, R.; Summers, D.; Chau, N.V.V.; Dalli, J.; Thwaites, G.E. A randomized double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV uninfected adults. eLife, 2018, 7e33478
Gold, B.; Pingle, M.; Brickner, S.J.; Shah, N.; Roberts, J.; Rundell, M.; Bracken, W.C.; Warrier, T.; Somersan, S.; Venugopal, A.; Darby, C.; Jiang, X.; Warren, J.D.; Fernandez, J.; Ouerfelli, O.; Nuermberger, E.L.; Cunningham-Bussel, A.; Ratha, P.; Chidawanyika, T.; Deng, H.; Realubit, R.; Glickman, J.F.; Nathan, C.F. Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials. Proc. Natl. Acad. Sci. USA, 2012, 109(40), 16004-16011.
Guzman, J.D.; Evangelopoulos, D.; Gupta, A.; Birchall, K.; Mwaigwisya, S.; Saxty, B.; McHugh, T.D.; Gibbons, S.; Malkinson, J.; Bhakta, S. Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay. BMJ, 2013, 3e002672
Tonby, K.; Wergeland, I.; Lieske, N.V.; Kvale, D.; Tasken, K.; Dyrhol-Riise, A.M. The COX- inhibitor indomethacin reduces Th1 effector and T regulatory cells in vitro in Mycobacterium tuberculosis infection. BMC Infect. Dis., 2016, 16, 599.
Vilaplana, C.; Marzo, E.; Tapia, G.; Diaz, J.; Garcia, V.; Cardona, P.J. Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis. J. Infect. Dis., 2013, 208, 199-202.
Dutta, N.K.; Mazumdar, K.; Dastidar, S.G.; Park, J.H. Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice. Int. J. Antimicrob. Agents, 2007, 30, 336-340.
Misra, U.K.; Nair, J.K.P.P. Role of aspirin in tuberculous meningitis: A randomized open label placebo controlled trial. J. Neurol. Sci., 2010, 293, 12-17.
Dutta, N.K.; Kumar, K.A.; Mazumdar, K.; Dastidar, S.G. In vitro and in vivo antimycobacterial activity of antiinflammatory drug, diclofenac sodium. Indian J. Exp. Biol., 2004, 42, 922-227.
Shirin, H.; Moss, S.F.; Kancherla, S.; Kancherla, K.; Holt, P.R.; Weinstein, I.B.; Sordillo, E.M. Non-steroidal anti-inflammatory drugs have bacteriostatic and bactericidal activity against Helicobacter pylori. J. Gastroenterol. Hepatol., 2006, 21, 1388-1393.

© 2022 Bentham Science Publishers | Privacy Policy