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Oxidative Stress as a Determinant of Antimicrobial Action, Resistance, and Treatment

  • Satabdi Banerjee
  • Suman K. NandyEmail author
  • Sajal Chakraborti
Chapter

Abstract

Multidrug resistance of bacterial strains due to inappropriate use of antibiotics is a great concern of current healthcare management. In the last century, the antibiotic research was mainly focused toward synthesis of new drugs for the traditional targets such as cell wall, protein, and DNA synthesis as well as understanding the bacterial counter strategies, namely, target modification, inactivation of drug, alteration of membrane permeability, active efflux of drug, etc. The shift of the paradigm of antibiotics research toward bacterial response to antibiotic action has recognized a common pathway of bactericidal antibiotic-induced oxidative stress-mediated cell killing. All bactericidal antibiotics, but not the bacteriostatic one, hyperactivate the citric acid cycle and electron transport chain and open the flood gate of reactive oxygen species (ROS) generation including the formation of highly toxic hydroxyl radical through Fenton reaction. ROS causes severe cellular damage to the biomolecules by lipid peroxidation, carbonylation of protein, and DNA strand breakage eventually leading to cell death. Bacterial stress response mechanisms counter the oxidative stress through active drug efflux, metabolic pathway modifications, synthesis of antioxidants, and SOS repair network, which additionally help microorganisms to acquire and propagate resistance. New treatment strategies are devised on pathogen-to-pathogen basis to overturn the resistance and potentiate the bactericidal action of antibiotics by targeting the SOS response regulatory proteins as well as increasing the ROS level at the site of infection by delivery of localized species-specific metabolites and antimicrobial agents.

Keywords

Drug resistance Antibiotic Bactericidal Oxidative stress ROS 

Notes

Acknowledgments

Thanks are due to the Department of Biotechnology, Ministry of Science and Technology, Government of India, for the funding and Bioinformatics Centre (BIF), NEHU, Tura Campus, for providing the infrastructure facility.

References

  1. 1.
    Fleming A (1929) On antibacterial action of culture of penicillium, with special reference to their use in isolation of B. influenzae. Br J Exp Pathol 10:226–236PubMedCentralPubMedGoogle Scholar
  2. 2.
    Fleming A (1964) Penicillin. In: Nobel lectures, physiology or medicine 1942–1962. Elsevier Publishing Company, AmsterdamGoogle Scholar
  3. 3.
    Munita JM, Arias CA (2016) Mechanisms of antibiotic resistance. Microbiol Spectr 4(2).  https://doi.org/10.1128/microbiolspec.VMBF-0016-2015
  4. 4.
    Poole K (2012) Bacterial stress responses as determinants of antimicrobial resistance. J Antimicrob Chemother 67(9):2069–2089CrossRefGoogle Scholar
  5. 5.
    Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130:797–810CrossRefGoogle Scholar
  6. 6.
    Kohanski MA, Dwyer DJ, Collins JJ (2010) How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 8(6):423CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Tran TD, Kwon HY, Kim EH, Kim KW, Briles DE, Pyo S, Rhee DK (2011) Decrease in penicillin susceptibility by heat shock protein ClpL in Streptococcus pneumoniae. Antimicrob Agents Chemother.  https://doi.org/10.1128/AAC.01383-10
  8. 8.
    Walsh C (2000) Molecular mechanisms that confer antibacterial drug resistance. Nature 406(6797):775–781CrossRefGoogle Scholar
  9. 9.
    Kimura KI, Ikeda Y, Kagami S, Yoshihama M, Suzuki K, Osada H, Isono K (1998) Selective inhibition of the bacterial peptidoglycan biosynthesis by the new types of liposidomycins. J Antibiot (Tokyo) 51(12):1099–1104CrossRefGoogle Scholar
  10. 10.
    Storm DR (1974) Mechanism of bacitracin action: a specific lipid-peptide interaction. Ann N Y Acad Sci 235(1):387–398CrossRefGoogle Scholar
  11. 11.
    Nelson ML, Grier MC, Barbaro SE, Ismail MY (2009) Polyfunctional antibiotics affecting bacterial membrane dynamics. Antiinfect Agents Med Chem 8(1):3–16CrossRefGoogle Scholar
  12. 12.
    Davis BD, Chen LL, Tai PC (1986) Misread protein creates membrane channels: an essential step in the bactericidal action of aminoglycosides. Proc Natl Acad Sci U S A 83:6164–6168CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    McCoy LS, Xie Y, Tor Y (2011) Antibiotics that target protein synthesis. Wiley Interdiscip Rev RNA 2(2):209–232CrossRefGoogle Scholar
  14. 14.
    Bhattacharjee MK (2016) Antibiotics that inhibit protein synthesis. In: Chemistry of antibiotics and related drugs. Springer, pp 129–151Google Scholar
  15. 15.
    Fàbrega A, Madurga S, Giralt E, Vila J (2009) Mechanism of action of and resistance to quinolones. Microb Biotechnol 2(1):40–61CrossRefGoogle Scholar
  16. 16.
    Howard BM, Pinney RJ, Smith JT (1993) Function of the SOS process in repair of DNA damage induced by modern 4-quinolones. J Pharm Pharmacol 45:658–662CrossRefGoogle Scholar
  17. 17.
    Cirz RT, Chin JK, Andes DR, de Crécy-Lagard V, Craig WA, Romesberg FE (2005) Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol 3:e176CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Floss HG, Yu TW (2005) Rifamycin mode of action, resistance, and biosynthesis. Chem Rev 105(2):621–632CrossRefGoogle Scholar
  19. 19.
    Murima P, McKinney JD, Pethe K (2014) Targeting bacterial central metabolism for drug development. Cell Chem Biol 21(11):1423–1432Google Scholar
  20. 20.
    Prescott JF (2013) Sulfonamides, diaminopyrimidines, and their combinations. In: Giguère S, Prescott JF, Dowling PM (eds) Antimicrobial therapy in veterinary medicine. Wiley, Hoboken, pp 279–294CrossRefGoogle Scholar
  21. 21.
    Liou JW, Hung YJ, Yang CH, Chen YC (2015) The antimicrobial activity of gramicidin a is associated with hydroxyl radical formation. PLoS One 10(1):e0117065CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Thomas VC, Kinkead LC, Janssen A, Schaeffer CR, Woods KM, Lindgren JK, Peaster JM, Chaudhari SS, Sadykov M, Jones J, AbdelGhani SM (2013) A dysfunctional tricarboxylic acid cycle enhances fitness of Staphylococcus epidermidis during β-lactam stress. MBio 4(4):e00437–e00413PubMedGoogle Scholar
  23. 23.
    Duan X, Huang X, Wang X, Yan S, Guo S, Abdalla AE, Huang C, Xie J (2016) L-serine potentiates fluoroquinolone activity against Escherichia coli by enhancing endogenous reactive oxygen species production. J Antimicrob Chemother 71(8):2192–2199CrossRefGoogle Scholar
  24. 24.
    Choi H, Yang Z, Weisshaar JC (2015) Single-cell, real-time detection of oxidative stress induced in Escherichia coli by the antimicrobial peptide CM15. Proc Natl Acad Sci U S A 112(3):E303–E310CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Páez PL, Becerra MC, Albesa I (2010) Antioxidative mechanisms protect resistant strains of Staphylococcus aureus against ciprofloxacin oxidative damage. Fundam Clin Pharmacol 24(6):771–776CrossRefGoogle Scholar
  26. 26.
    Schurek KN, Marr AK, Taylor PK, Wiegand I, Semenec L, Khaira BK, Hancock RE (2008) Novel genetic determinants of low-level aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 52(12):4213–4219CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Girgis HS, Hottes AK, Tavazoie S (2009) Genetic architecture of intrinsic antibiotic susceptibility. PLoS One 4(5):e5629CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ladjouzi R, Bizzini A, van Schaik W, Zhang X, Rincé A, Benachour A, Hartke A (2015) Loss of antibiotic tolerance in sod-deficient mutants is dependent on the energy source and arginine catabolism in enterococci. J Bacteriol:JB-00389.  https://doi.org/10.1128/JB.00389-15
  29. 29.
    Imlay JA (2003) Pathways of oxidative damage. Annu Rev Microbiol 57(1):395–418CrossRefGoogle Scholar
  30. 30.
    Kohanski MA, Dwyer DJ, Wierzbowski J, Cottarel G, Collins JJ (2008) Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death. Cell 135(4):679–690CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu X, De Wulf P (2004) Probing the ArcA-P modulon of Escherichia coli by whole genome transcriptional analysis and sequence recognition profiling. J Biol Chem 279(13):12588–12597CrossRefGoogle Scholar
  32. 32.
    Belenky P, Jonathan DY, Porter CB, Cohen NR, Lobritz MA, Ferrante T, Jain S, Korry BJ, Schwarz EG, Walker GC, Collins JJ (2015) Bactericidal antibiotics induce toxic metabolic perturbations that lead to cellular damage. Cell Rep 13(5):968–980CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Neeley WL, Essigmann JM (2006) Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol 19(4):491–505CrossRefGoogle Scholar
  34. 34.
    Feld L, Knudsen GM, Gram L (2012) Bactericidal antibiotics do not appear to cause oxidative stress in Listeria monocytogenes. Appl Environ Microbiol:AEM-00324.  https://doi.org/10.1128/AEM.00324-12
  35. 35.
    Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Zimmerman T, De La Campa AG (2015) Reactive oxygen species contribute to the bactericidal effects of the fluoroquinolone moxifloxacin in Streptococcus pneumoniae. Antimicrob Agents Chemother:AAC-02299.  https://doi.org/10.1128/AAC.02299-15
  36. 36.
    Liu Y, Imlay JA (2013) Cell death from antibiotics without the involvement of reactive oxygen species. Science 339(6124):1210–1213CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Keren I, Wu Y, Inocencio J, Mulcahy LR, Lewis K (2013) Killing by bactericidal antibiotics does not depend on reactive oxygen species. Science 339(6124):1213–1216CrossRefGoogle Scholar
  38. 38.
    Nguyen D, Joshi-Datar A, Lepine F, Bauerle E, Olakanmi O, Beer K, McKay G, Siehnel R, Schafhauser J, Wang Y, Britigan BE (2011) Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334(6058):982–986CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Allison KR, Brynildsen MP, Collins JJ (2011) Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473(7346):216CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lobritz MA, Belenky P, Porter CB, Gutierrez A, Yang JH, Schwarz EG, Dwyer DJ, Khalil AS, Collins JJ (2015) Antibiotic efficacy is linked to bacterial cellular respiration. Proc Natl Acad Sci U S A 201509743Google Scholar
  41. 41.
    Brochmann RP, Toft A, Ciofu O, Briales A, Kolpen M, Hempel C, Bjarnsholt T, Høiby N, Jensen PØ (2014) Bactericidal effect of colistin on planktonic Pseudomonas aeruginosa is independent of hydroxyl radical formation. Int J Antimicrob Agents 43(2):140–147CrossRefGoogle Scholar
  42. 42.
    Liu Y, Liu X, Qu Y, Wang X, Li L, Zhao X (2012) Inhibitors of ROS accumulation delay and/or reduce lethality of several anti-staphylococcus agents. Antimicrob Agents Chemother:AAC-00754Google Scholar
  43. 43.
    Dridi B, Lupien A, Bergeron MG, Leprohon P, Ouellette M (2015) Antibiotic-induced oxidative stress responses between laboratory and clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother:AAC-00316Google Scholar
  44. 44.
    Lee HH, Molla MN, Cantor CR, Collins JJ (2010) Bacterial charity work leads to population-wide resistance. Nature 467(7311):82CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gu M, Imlay JA (2011) The SoxRS response of Escherichia coli is directly activated by redox-cycling drugs rather than by superoxide. Mol Microbiol 79(5):1136–1150CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Chen PR, Bae T, Williams WA, Duguid EM, Rice PA, Schneewind O, He C (2006) An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus. Nat Chem Biol 2(11):591CrossRefGoogle Scholar
  47. 47.
    Chen PR, Nishida S, Poor CB, Cheng A, Bae T, Kuechenmeister L, Dunman PM, Missiakas D, He C (2009) A new oxidative sensing and regulation pathway mediated by the MgrA homologue SarZ in Staphylococcus aureus. Mol Microbiol 71(1):198–211CrossRefGoogle Scholar
  48. 48.
    Chen H, Hu J, Chen PR, Lan L, Li Z, Hicks LM, Dinner AR, He C (2008) The Pseudomonas aeruginosa multidrug efflux regulator MexR uses an oxidation-sensing mechanism. Proc Natl Acad Sci U S A 105(36):13586–13591CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mosel M, Li L, Drlica K, Zhao X (2013) Superoxide-mediated protection of Escherichia coli from antimicrobials. Antimicrob Agents Chemother:AAC-00754Google Scholar
  50. 50.
    Mikkelsen H, Swatton JE, Lilley KS, Welch M (2010) Proteomic analysis of the adaptive responses of Pseudomonas aeruginosa to aminoglycoside antibiotics. FEMS Microbiol Lett.  https://doi.org/10.1111/j.1574-6968.2009.01729.x
  51. 51.
    Van Acker H, Sass A, Bazzini S, De Roy K, Udine C, Messiaen T, Riccardi G, Boon N, Nelis HJ, Mahenthiralingam E, Coenye T (2013) Biofilm-grown Burkholderia cepacia complex cells survive antibiotic treatment by avoiding production of reactive oxygen species. PLoS One 8(3):e58943CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ahn S, Jung J, Jang IA, Madsen EL, Park W (2016) Role of glyoxylate shunt in oxidative stress response. J Biol Chem:jbc–M115Google Scholar
  53. 53.
    Knudsen GM, Fromberg A, Ng Y, Gram L (2016) Sublethal concentrations of antibiotics cause shift to anaerobic metabolism in listeria monocytogenes and induce phenotypes linked to antibiotic tolerance. Front Microbiol 7:1091CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Shatalin K, Shatalina E, Mironov A, Nudler E (2011) H2S: a universal defense against antibiotics in bacteria. Science 334(6058):986–990CrossRefGoogle Scholar
  55. 55.
    Kohanski MA, DePristo MA, Collins JJ (2010) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37(3):311–320CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Jee J, Rasouly A, Shamovsky I, Akivis Y, Steinman SR, Mishra B, Nudler E (2016) Rates and mechanisms of bacterial mutagenesis from maximum-depth sequencing. Nature 534(7609):693CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yang W, Woodgate R (2007) What a difference a decade makes: insights into translesion DNA synthesis. Proc Natl Acad Sci U S A 104(40):15591–15598CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Tang M, Pham P, Shen X, Taylor JS, O’donnell M, Woodgate R, Goodman MF (2000) Roles of E. coli DNA polymerases IV and V in lesion-targeted and untargeted SOS mutagenesis. Nature 404(6781):1014CrossRefGoogle Scholar
  59. 59.
    Miller C, Thomsen LE, Gaggero C, Mosseri R, Ingmer H, Cohen SN (2004) SOS response induction by ß-lactams and bacterial defense against antibiotic lethality. Science 305(5690):1629–1631CrossRefGoogle Scholar
  60. 60.
    Maiques E, Úbeda C, Campoy S, Salvador N, Lasa Í, Novick RP, Barbé J, Penadés JR (2006) β-lactam antibiotics induce the SOS response and horizontal transfer of virulence factors in Staphylococcus aureus. J Bacteriol 188(7):2726–2729CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hocquet D, Llanes C, Thouverez M, Kulasekara HD, Bertrand X, Plésiat P, Mazel D, Miller SI (2012) Evidence for induction of integron-based antibiotic resistance by the SOS response in a clinical setting. PLoS Pathog 8(6):e1002778CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Händel N, Hoeksema M, Mata MF, Brul S, Ter Kuile BH (2016) Effects of stress, reactive oxygen species, and the SOS response on de novo acquisition of antibiotic resistance in Escherichia coli. Antimicrob Agents Chemother 60(3):1319–1327CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Van Acker H, Coenye T (2017) The role of reactive oxygen species in antibiotic-mediated killing of bacteria. Trends Microbiol 25(6):456–466CrossRefGoogle Scholar
  64. 64.
    Brynildsen MP, Winkler JA, Spina CS, MacDonald IC, Collins JJ (2013) Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production. Nat Biotechnol 31(2):160CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Meylan S, Andrews IW, Collins JJ (2018) Targeting antibiotic tolerance, pathogen by pathogen. Cell 172(6):1228–1238CrossRefGoogle Scholar
  66. 66.
    Mosovsky K, Silva E, Troyer R, Propst-Graham K, Dow S (2014) Interaction of IFN-γ induced reactive oxygen species with ceftazidime leads to synergistic killing of intracellular Burkholderia. Antimicrob Agents Chemother:AAC-02781Google Scholar
  67. 67.
    Recacha E, Machuca J, de Alba PD, Ramos-Güelfo M, Docobo-Pérez F, Rodriguez-Beltrán J, Blázquez J, Pascual A, Rodríguez-Martínez JM (2017) Quinolone resistance reversion by targeting the SOS response. MBio 8(5):e00971–e00917CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Mo CY, Manning SA, Roggiani M, Culyba MJ, Samuels AN, Sniegowski PD, Goulian M, Kohli RM (2017) Systematically altering bacterial SOS activity under stress reveals therapeutic strategies for potentiating antibiotics. mSphere 1(4):e00163–e00116Google Scholar
  69. 69.
    Lu TK, Collins JJ (2009) Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy. Proc Natl Acad Sci U S A 106(12):4629–4634CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Mo CY, Culyba MJ, Selwood T, Kubiak JM, Hostetler ZM, Jurewicz AJ, Keller PM, Pope AJ, Quinn A, Schneck J, Widdowson KL (2017) Inhibitors of LexA autoproteolysis and the bacterial SOS response discovered by an academic–industry partnership. ACS Infect Dis 4(3):349–359CrossRefGoogle Scholar
  71. 71.
    Braff D, Shis D, Collins JJ (2016) Synthetic biology platform technologies for antimicrobial applications. Adv Drug Deliv Rev 105:35–43CrossRefGoogle Scholar
  72. 72.
    Jijie R, Barras A, Teodorescu F, Boukherroub R, Szunerits S (2017) Advancements on the molecular design of nanoantibiotics: current level of development and future challenges. Mol Syst Des Eng 2(4):349–369CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Satabdi Banerjee
    • 1
  • Suman K. Nandy
    • 2
    Email author
  • Sajal Chakraborti
    • 3
  1. 1.Department of Environmental ManagementWilliam Carey UniversityShillongIndia
  2. 2.Bioinformatics Infrastructure Facility (BIF)North-Eastern Hill University (NEHU)TuraIndia
  3. 3.Department of Biochemistry and BiophysicsUniversity of KalyaniKalyaniIndia

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