Immune system as a new therapeutic target for antibiotics


Since the discovery of penicillin by Fleming in 1928, the knowledge of the antibiotics’ spectrum and mechanism of action has been steadily increasing. Antibiotics became an effective tool in the fight against many pathogens, changing the prognosis of outcome for many serious diseases. It is already known that antibiotics not only have the antibacterial activity, but many of theme.g. macrolides, sulphonamides and tetracyclineshave immunomodulating effect, affecting functions of lymphocytes, macrophages and costimulatory molecules, macrophage migration and phagocytosis, as well as proinflammatory cytokine secretion. The expanding knowledge of the effects of antibiotics on the immune system has brought with it new applications of antibiotics in organ transplantation, invasive cardiology and treatment of autoimmune diseases such as rheumatoid arthritis or asthma.

Share and Cite:

Kwiatkowska, B. , Maslinska, M. , Przygodzka, M. , Dmowska-Chalaba, J. , Dabrowska, J. and Sikorska-Siudek, K. (2013) Immune system as a new therapeutic target for antibiotics. Advances in Bioscience and Biotechnology, 4, 91-101. doi: 10.4236/abb.2013.44A013.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Pasquale, T.R. and Tan, J.S. (2005) Nonantimicrobial effects of antibacterial agents. Clinical Infectious Diseases, 40, 127-135.
[2] Guz, K. and Bugla-Plaskońska, G. (2007) The immunomodulatory and anti-inflammatory properties of diferent antimicrobial agents. Postepy Higieny i Medycyny Doswiadczalnej, 61, 828-837.
[3] Kwiatkowska, B. and Mallińska, M. (2012) Macrolide therapy in chronic inflammatory diseases. Mediators of Inflammation, 2012, Article ID: 636157. doi:10.1155/2012/636157
[4] Brooks, B.M., Flanagan, B.F., Thomas, A.L. and Coleman, J.W. (2001) Penicillin conjugates to interferon-gamma and reduces its activity: A novel drug-cytokine interaction. Biochemical and Biophysical Research Communications, 288, 1175-1181.
[5] Mangano, K., Quattrocchi, C., Scalia, G., Speciale, A., Nicoletti, G. and Di Marco, R. (2006) Immunomodulatory properties of cefaclor: In vivo effect on cytokine release and lymphoproliferative response in rats. Journal of Chemotherapy, 18, 641-647.
[6] Tauber, S.C. and Nau, R. (2008) Immunomodulatory properties of antibiotics. Current Molecular Pharmacology, 1, 68-79.
[7] Wenisch, C., Parschalk, B., Hasenhündl, M., Wiesinger, E. and Graninger, W. (1995) Effect of cefodizime and ceftriaxone on phagocytic function in patients with severe infections. Antimicrobial Agents and Chemotherapy, 39, 672-676. doi:10.1128/AAC.39.3.672
[8] Alekshun, M.N. (2005) New advances In antibiotic development and discovery. Expert Opinion on Investigational Drugs, 14, 117-134. doi:10.1517/13543784.14.2.117
[9] Wilson, D.N. (2009) The A-Z of bacterial translation inhibitors. Critical Reviews in Biochemistry and Molecular Biology, 44, 393-433. doi:10.3109/10409230903307311
[10] Kanoh, S. and Rubin, B.K. (2010) Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clinical Microbiology Reviews, 23, 590-615. doi:10.1128/CMR.00078-09
[11] Suzaki, H., Asano, K., Ohki, S., et al. (1999) Supressive activity of a macrolide antibiotic, roxitromycin, on proinflammatory cytokine production in vitro and in vivo. Mediators of Inflammation, 8, 199-204. doi:10.1080/09629359990351
[12] Shimane, T., Asano, K., Suzuki, M., et al. (2001) Influence of a macrolide antibiotic, roxitromycin, on mast cell growth and activation in vitro. Mediators of Inflammation, 10, 323- 332. doi:10.1080/09629350120102343
[13] Schultz, M.J., Speelman, P., Hack, C.R., et al. (2000) Intravenous infusion of erythromycin inhibits CXC chemokine production, but augments neutrophil degranulation in whole blood stimulated with Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy, 46, 235- 240. doi:10.1093/jac/46.2.235
[14] Matsuoka, N., Eguchi, K., Kawakami, A., et al. (1996) Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells. Clinical & Experimental Immunology, 104, 501-508. doi:10.1046/j.1365-2249.1996.46752.x
[15] Keicho, N., Kudoh, S., Yotsumo, H., et al. (1993) Antilymphocytic activity of erythromycin distinct from that of FK506 or cyclosporine A. The Journal of Antibiotics, 46, 1406-1413. doi:10.7164/antibiotics.46.1406
[16] Sato, E., Nelson, D.K., Koyama, J., et al. (2000) Erythromycin modulates eosinophil chemotactic cytokine production by lung fibroblasts in vitro. Antimicrobial Agents and Chemotherapy, 45, 401-406. doi:10.1128/AAC.8.2.401-406.2001
[17] Ogrendik, M. (2009) Efficacy of roxitromycin in adult patients with rheumatoid arthritis who had not received disease-modifying antirheumatic drugs: A 3-month, randomized, double-blind, placebo-controlled trial. Clinical Therapeutics, 31, 1754-1764. doi:10.1016/j.clinthera.2009.08.014
[18] Oyama, K., Sakuta, T., Matsushita, K., Maruyama, I., Nagaoka, S. and Torii, M. (2000) Effects of roxithromycin on tumor necrosis factor-alpha-induced vascular endothelial growth factor expression in human periodontal ligament cells in culture. Journal of Periodontology, 71, 1546- 1553doi:10.1902/jop.2000.71.10.1546
[19] Ogrendik, M. (2007) Effects of clarithromycin in patients with active rheumatoid arthritis. Current Medical Research and Opinion, 23, 515-522. doi:10.1185/030079906X167642
[20] Sawiola, G., Benucci, M., Abdi-Ali, L., Baiardi, P., Manferdi, M., Bucci, M. and Cirino, G. (2010) Clarithromycin in adult-onset Still’s disease: A study of 6 cases. Rheumatology International, 30, 555-560. doi:10.1007/s00296-009-1277-9
[21] Thanou-Stavraki, A., Aberle, T., Aksentijevich, I., Bane, B.L. and Harley, J.B. (2011) Clarithromycin in adult-on- set still’s disease: A potentially useful therapeutic. Journal of Clinical Rheumatology, 17, 373-376. doi:10.1097/RHU.0b013e3182320680
[22] Carevic, O. and Djokic, S. (1988) Comparative studies on the effects of erythromycin A and azithromycin upon extracellular release of lysosomal enzymes in inflammatory processes. Agents and Actions, 25, 124-131. doi:10.1007/BF01969103
[23] Mencarelli, A., Distrutti, E., Renga, B., et al. (2011) Development of non-anticiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis. European Journal of Pharmacology, 665, 29-39.
[24] Eisen, H.J., Tuzcu, E.M., Dorent, R., et al. (2003) Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. The New England Journal of Medicine, 349, 847-858.
[25] Blagosklonny, M.V. (2011) Progeria, rapamycin and normal aging: Recent breakthrough. Aging, 3, 685-691.
[26] Calleja, C., Pascussi, J.M., Mani, J.C., Maurel, P. and Vilarem, M.J. (1998) The antibiotic rifampicin is a nonsteroidal ligand and activator of the human glucocorticoid receptor. Nature Medicine, 4, 92-96. doi:10.1038/nm0198-092
[27] Herr, A.S., Wochnik, G.M., Rosenhagen, M.C., Holsboer, F. and Rein, T. (2000) Rifampicin is not an activator of glucocorticoid receptor. Molecular Pharmacology, 57, 732- 737.
[28] Sapadin, A.N. and Fleischmajer, R. (2006) Tetracyclines: Nonantibiotic properties and their clinical implications. Journal of the American Academy of Dermatology, 54, 258-265. doi:10.1016/j.jaad.2005.10.004
[29] Golub, L.M., Lee, H.M., Lehrer, G., Nemiroff, A., Mc- Namara, T.F., Kaplan, R., et al. (1983) Minocycline reduses gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. Journal of Periodontal Research, 18, 516-526. doi:10.1111/j.1600-0765.1983.tb00388.x
[30] Kloppenburg, M., Verweij, C.L., Miltenburg, A.M.M., Verhoeven, A.J., Daha, M.R., Dijkmans, B.A.C. and Breedveld, F.C. (1995) The influence of tetracyclines on T cell activation. Clinical & Experimental Immunology, 102, 635-641. doi:10.1111/j.1365-2249.1995.tb03864.x
[31] Greenwald, R.A., Golub, L.M., Lavities, B., Ramamurthy, N.S., Gruber, B., Laskin, R.S. and McNamara, T.F. (1987) Tetracyclines inhibit human synovial collagenase in Vivo and in Vitro. The Journal of Rheumatology, 14, 28-32.
[32] Schnabel, L.V., Papich, M.G., Watts, A.E. and Fortier L.A. (2010) Orally administred doxycycline accumulates in synovial fluid compared to plasma. Equine Veterinary Journal, 42, 208-210. doi:10.2746/042516409X478514
[33] Kloppenburg, M., Breedveld, F.C., Terwiel, J.Ph., Mallee, C. and Dijkmans, B.A.C. (1994) Minocycline in active rheumatoid arthritis. A double-blind, plcebo-controlled trial. Arthritis & Rheumatism, 37, 629-636. doi:10.1002/art.1780370505
[34] O’Dell, J.R., Haire, C.E., Palmer, W., Drymalski, W., Wees, S., Blakely, K., Churchill, M., Eckhoff, P.J., Weaver, A., Doud, D., Erikson, N., Diez, F., Olson, R., Maloley, P., Klassen, L.W. and Moore, G. (1997) Reatment of early rheumatoid arthritis with minocycline or placebo. Result of a randomized, double blind, placebo-controlled trial. Arthritis & Rheumatism, 40, 842-848. doi:10.1002/art.1780400510
[35] Stone, M., Fortin, P.R., Pacheco-Tena, C. and Inman, R.D. (2003) Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. The Journal of Rheumatology, 30, 2112-2122.
[36] O’Dell, J.R., Blakely, K.W., Mallek, J.A., Eckhoff, P.J., Leff, R.D., Sems, K.M., Fernandez, A.M., Palmer, W.R., Klassen, L.W., Paulsen, G.A., Hair, C.E. and Moore G.F. (2001) Treatment of early seropositive rheumatoid arthritis: A two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis & Rheumatism, 44, 2235-2241. doi:10.1002/1529-0131(200110)44:10<2235::AID-ART385>3.0.CO;2-A
[37] Laasila, K., Laasonen, L. and Leirisalo-Repo, M. (2003) Antibiotic treatment and long term prognosis of reactive arthritis. Annals of the Rheumatic Diseases, 62, 655-658. doi:10.1136/ard.62.7.655
[38] Yu, L.P., Smith, G.N., Brandt, K.D., Myers, S.L., O’Connor, B.L. and Brandt, D.A. (1992) Reduction of the severity of cannine osteoartthritis by prophylactic treatment with oral doxycycline. Arthritis & Rheumatism, 35, 1150- 1159. doi:10.1002/art.1780351007
[39] Lokeshwar, B.L. (2001) Chemically modified non antimicrobial tetracyclines are multifunctional drugs against advanced cancers. Pharmacolgical Research, 63, 146- 150. doi:10.1016/j.phrs.2010.11.003
[40] Lokeshwar, B.L., Houston-Clark, H.L., Selzer, M.G., Block, N.L. and Golub, L.M. (1998) Potential application of a chemically modified non antimicrobial tetracycline (CMT- 3) against metastatic prostate cancer. Advances in Dental Research, 12, 97-102.
[41] Castro, M.M., Rizzi, E., Figueiredo-Lopes, L., Fernandes, K., Bendhack, L.M., Pitol, D.L., et al. (2008) Aetalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis, 198, 320-331. doi:10.1016/j.atherosclerosis.2007.10.011
[42] Creemers, E.E., Cleutjens, J.P., Smith, J.F. and Daemen, M.J. (2001) Matrix metalloproteinase inhibition after myocardial infarction: A new approach to prevent heart failure? Circulation Research, 89, 201-210. doi:10.1161/hh1501.094396
[43] Castro, M.M., Kandasamy, A.D., Youssef, N. and Schulz, R. (2011) Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases. Pharmacologycal Research, 64, 551-560. doi:10.1016/j.phrs.2011.05.005
[44] Cena, J.J., lalu, M.M., Cho, W.J., Chow, A.K., Bagdan, M.L., Daniel, E.E., et al. (2009) Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia. American Journal of Physiology-Heart and Circulatory Physiology, 298, 45- 51. doi:10.1152/ajpheart.00273.2009
[45] Li, M., Ona, V.O., Chen, M., Kaul, M., Tenneti, L., Zhang, X., et al. (2009) Functional role and therapeutic implications of neuronal caspase-1 and-3 in a mouse model of traumatic spinal cord injury. Neuroscience, 99, 333-342. doi:10.1016/S0306-4522(00)00173-1
[46] Sanchez, M.R.O., Ona, V.O, Li, M. and Friedlander, R.M. (2001) Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage and neurogical dysfunction. Neurosurgery, 48, 1393-1401.
[47] Lai, A.Y. and Todd, K.G. (2006) Hipoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines. Glia, 53, 809-816. doi:10.1002/glia.20335
[48] Brundula, V., Rewcastle, N.B., Metz, L.M., Bernard, C.C. and Yong, V.W. (2002) Targeting leucocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis. Brain, 125, 1297-1308. doi:10.1093/brain/awf133
[49] Bastos, L.F.S., De Oliveira, A.C.P., Watkins, L.R., Moraes, M.F.D. and Coelho, M.M. (2012) Tetracyclines and pain. Naunyn-Schmiedeberg’s Archives of Pharmacology, 385, 225-241. doi:10.1007/s00210-012-0727-1
[50] Miyazaki, E., Ando, M., Fukami, T., Nureki, S., Eishi, E., Kumamoto, T. (2008) Minocycline for the treatment of sarcoidosis: In the mechanism of action immunomodulating or antimicrobial effect? Clinical Rheumatology, 27, 1195-1197. doi:10.1007/s10067-008-0903-3
[51] Agostini, C., Cassatella, M., Zembello, R., et al. (1998) Involment if the IP-10 chemokine in sarcoid granulomatous reaction. Journal of Immunology, 161, 6413-6420.
[52] Le, C.H., Morales, A. and Trentham, D.E. (1998) Minocycline in early diffuse scleroderma. Lancet, 28, 1755- 1756.
[53] Singer, I. and Rosenberg, D. (1973) Demociline induced nephrogenic diabetes insipidus: In vivo and in vitro studies. Annals of Internal Medicine, 79, 679-683. doi:10.7326/0003-4819-79-5-679
[54] Cherrill, D.A., Stote, R.M., Birge, J.R. and Singe, I. (1975) Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion. Annals of Internal Medicine, 83, 654-656. doi:10.7326/0003-4819-83-5-654
[55] Kahn, A.A., Slifer, T.R. and Remington, J.S. (1998) Effect of Trovafloxacin on production of cytokinez by human monocytes Antimicrob. Agents Chemother, 42, 1713- 1717.
[56] Lahat, G., Halperin, D., Barazovsky, E., Shalit, I. and Rabau, M. (2007) Immunomodulatory effects of ciprofloxacin in TNBS-induced colitis in mice. Inflammatory Bowel Diseases, 13, 557-565.
[57] Hall, I.H., Schwab, U.E., Ward, E.S. and Ives, T.J. (2003) Effects of moxifloxacin in zymogen A or S. aureus stimulated human THP-1monocytes on the inflammatory process and the spread of infection. Life Sciences, 73, 2675-2685. doi:10.1016/S0024-3205(03)00611-8
[58] Fernández, O. (2011) Oral laquinimod treatment in multiple sclerosis. Neurologia, 26, 111-117.
[59] Gemmell, C.G., Peterson, Ph.K., Schmeling, D. and Kim, Y. (1981) Potentiation of opsonization and phagocytosis of Streptococcus pyogenes following growth in the presence of clindamycin. The Journal of Clinical Investigation, 67, 1249-1256.
[60] Takahashi, G., Sato, N., Yaegashi, Y., et al. (2010) Effect of linezolid on cytokine production capacity and plasma endotoxin levels in response to lipopolysaccharide stimulation of whole blood. Journal of Infection and Chemotherapy, 16, 94-99.
[61] Garcia-Roca, P., Mancilla-Ramirez, J., Santos-Segura, A., Fernández-Avilés, M. and Calderon-Jaimes. E. (2006) Linezolid diminishes inflammatory cytokine production from human peripheral blood mononuclear cells. Archives of Medical Research, 37, 31-35.
[62] Pichereau, S., Moran, J.M.M., Hayney, M.S., Shukla, S.K., Sakoulas, G. and Rose W.E. (2012) Concentrationdependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells. Journal of Antimicrobial Chemotherapy, 67, 123-129.
[63] Müller, S., Eljack, S. and DelGaudio, J.M. (2011) Wegener’s Granulaomatosis. Head and Neck Pathology, 5, 268-272.
[64] Brom, C., Brom, J. and König, W. (1992) Neomycin induces stimulatory and inhibitory effects on leukotriene generation, guanine triphospatase activity, and actin polymeryzation within human neutrophils. Immunology, 75, 150-156.
[65] Bendtzen, K., Diamant, M. and Faber, V. (1990) Fusidic acid, an immunosuppressive drug with functions similar to cyclosporin A. Cytokine, 2, 423-429.
[66] Osman, M.O., El-Sefi, T., Lausten, S.B., Jacobsen, N.O.G., Larsen, C.G. and Jensen, S.I. (1998) Sodium fusidate and the cytokine response in an experimental model of acute pancreatitis. British Journal of Surgery, 85, 1487-1492.
[67] Morikawa, K., Oseko, F.I., Morikawa, S. and Sawada, M. (1993) Immunosuppressive activity of fosfomycin on human T-lymphocyte function in Vitro. Antimicrobial Agents and Chemotherapy, 37, 2684-2687.
[68] Zeitlinger, M., Marsik, C., Steiner, I., Sauermann, R., Seir, K., Jilma, B., Wagner, O. and Joukhadar, C. (2007) Immunomodulatory effects of fosfomycin in an endotoxin model in human blood. The Journal of Antimicrobial Chemotherapy, 59, 219-223.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.