Sub-minimal inhibitory concentrations of fluoroquinolones in the environment: A trigger for the emergence of drug-resistant bacteria

Arash  Bakhshi; Farzaneh  Sedaghat; Mohammad-Esmaeil  Amini; Alireza  Samadnia; Hadi  Sedigh Ebrahim-Saraie

doi:10.61882/jcbior.5.3.217

Authors

Arash Bakhshi Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
Farzaneh Sedaghat Student Research Committee, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
Mohammad-Esmaeil Amini Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Alireza Samadnia Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
Hadi Sedigh Ebrahim-Saraie Department of Microbiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran https://orcid.org/0000-0001-8339-5199

DOI:

https://doi.org/10.61882/jcbior.5.3.217

Keywords:

Quinolones, Soil contamination, Antibiotic resistance, DNA damage, SOS response

Abstract

Fluoroquinolones represent a significant class of antimicrobial agents. These compounds are effective in the treatment of various enteric infections in veterinary medicine. The primary bacterial targets of quinolones are topoisomerase IV and DNA gyrase, enzymes essential for DNA replication and repair. A major public health concern is the potential transmission of fluoroquinolone-resistant bacteria from livestock to humans. The development of antimicrobial resistance in both animals and humans is interconnected. Multiple observational studies and randomized trials have established an association between the use of antibiotics in food animals and the emergence of antimicrobial-resistant bacteria. Fluoroquinolones induce DNA damage, leading to DNA strand breaks that activate the SOS response and various DNA repair pathways. The SOS system, a key component of the DNA repair machinery, plays a critical role in cell cycle regulation. Activation of this system initiates a cascade of signals within bacteria, resulting in enhanced pathogenicity. Through these signaling pathways, bacteria have evolved diverse mechanisms such as pathogenicity islands, biofilm formation, and toxin production. The presence of residual fluoroquinolones in livestock environments and animal production systems following veterinary use is associated with increased bacterial virulence. This review focuses on the impact of fluoroquinolone exposure at sub-minimal inhibitory concentrations on bacterial virulence and pathogenicity.

References

1. Deresinski S. Principles of antibiotic therapy in severe infections: optimizing the therapeutic approach by use of laboratory and clinical data. Clin Infect Dis. 2007;45(Suppl 3):S177-83.

DOI: 10.1086/519472 PMID: 17712744

2. Dadgostar P. Antimicrobial Resistance: Implications and Costs. Infect Drug Resist. 2019;12:3903-3910.

DOI: 10.2147/IDR.S234610 PMID: 31908502

3. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev. 1989;2(4):378-424.

DOI: 10.1128/CMR.2.4.378 PMID: 2680058

4. Chen FJ, Lo HJ. Molecular mechanisms of fluoroquinolone resistance. J Microbiol Immunol Infect. 2003;36(1):1-9.

PMID: 12741725

5. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74(3):417-33.

DOI: 10.1128/MMBR.00016-10 PMID: 20805405

6. Zieliński W, Korzeniewska E, Harnisz M, Drzymała J, Felis E, Bajkacz S. Wastewater treatment plants as a reservoir of integrase and antibiotic resistance genes - An epidemiological threat to workers and environment. Environ Int. 2021;156:106641.

DOI: 10.1016/j.envint.2021.106641 PMID: 34015664

7. Roberts MG, Burgess S, Toombs-Ruane LJ, Benschop J, Marshall JC, French NP. Combining mutation and horizontal gene transfer in a within-host model of antibiotic resistance. Math Biosci. 2021;339:108656. DOI: 10.1016/j.mbs.2021.108656 PMID: 34216634

8. Marshall BM, Levy SB. Food animals and antimicrobials: impacts on human health. Clin Microbiol Rev. 2011;24(4):718-33. DOI: 10.1128/CMR.00002-11 PMID: 21976606

9. Singer AC, Shaw H, Rhodes V, Hart A. Review of Antimicrobial Resistance in the Environment and Its Relevance to Environmental Regulators. Front Microbiol. 2016;7:1728.

DOI: 10.3389/fmicb.2016.01728 PMID: 27847505

10. Mesa Varona O, Chaintarli K, Muller-Pebody B, Anjum MF, Eckmanns T, Norström M, et al. Monitoring Antimicrobial Resistance and Drug Usage in the Human and Livestock Sector and Foodborne Antimicrobial Resistance in Six European Countries. Infect Drug Resist. 2020;13:957-993.

DOI: 10.2147/IDR.S237038 PMID: 32308439

11. Palma E, Tilocca B, Roncada P. Antimicrobial Resistance in Veterinary Medicine: An Overview. Int J Mol Sci. 2020;21(6):1914. DOI: 10.3390/ijms21061914 PMID: 32168903

12. Landers TF, Cohen B, Wittum TE, Larson EL. A review of antibiotic use in food animals: perspective, policy, and potential. Public Health Rep. 2012;127(1):4-22.

DOI: 10.1177/003335491212700103 PMID: 22298919

13. Basbas C, Aly S, Okello E, Karle BM, Lehenbauer T, Williams D, et al. Effect of Intramammary Dry Cow Antimicrobial Treatment on Fresh Cow's Milk Microbiota in California Commercial Dairies. Antibiotics (Basel). 2022;11(7):963.

DOI: 10.3390/antibiotics11070963 PMID: 35884217

14. Casseri E, Bulut E, Llanos Soto S, Wemette M, Stout A, Greiner Safi A, et al. Understanding Antibiotic Resistance as a Perceived Threat towards Dairy Cattle through Beliefs and Practices: A Survey-Based Study of Dairy Farmers. Antibiotics (Basel). 2022;11(8):997. DOI: 10.3390/antibiotics11080997

PMID: 35892387

15. Millanao AR, Mora AY, Villagra NA, Bucarey SA, Hidalgo AA. Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents. Molecules. 2021;26(23):7153.

DOI: 10.3390/molecules26237153 PMID: 34885734

16. Pham TDM, Ziora ZM, Blaskovich MAT. Quinolone antibiotics. Medchemcomm. 2019;10(10):1719-1739.

DOI: 10.1039/c9md00120d PMID: 31803393

17. Bradley JS, Jackson MA, Committee on Infectious Diseases, American Academy of Pediatrics. The use of systemic and topical fluoroquinolones. Pediatrics. 2011;128(4):e1034-45.

DOI: 10.1542/peds.2011-1496 PMID: 21949152

18. Fàbrega A, Madurga S, Giralt E, Vila J. Mechanism of action of and resistance to quinolones. Microb Biotechnol. 2009;2(1):40-61. DOI: 10.1111/j.1751-7915.2008.00063.x PMID: 21261881

19. Naeem A, Badshah SL, Muska M, Ahmad N, Khan K. The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity. Molecules. 2016;21(4):268.

DOI: 10.3390/molecules21040268 PMID: 27043501

20. Lungu IA, Moldovan OL, Biriș V, Rusu A. Fluoroquinolones Hybrid Molecules as Promising Antibacterial Agents in the Fight against Antibacterial Resistance. Pharmaceutics. 2022;14(8):1749. DOI: 10.3390/pharmaceutics14081749

PMID: 36015376

21. Jun C, Fang B. Current progress of fluoroquinolones-increased risk of aortic aneurysm and dissection. BMC Cardiovasc Disord. 2021;21(1):470. DOI: 10.1186/s12872-021-02258-1

PMID: 34583637

22. Idowu T, Schweizer F. Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities. Antibiotics (Basel). 2017;6(4):26.

DOI: 10.3390/antibiotics6040026 PMID: 29112154

23. Collignon P. Fluoroquinolone use in food animals. Emerg Infect Dis. 2005;11(11):1789-90; author reply 1790-2.

DOI: 10.3201/eid1111.040630 PMID: 16422004

24. Shams WE, Evans ME. Guide to selection of fluoroquinolones in patients with lower respiratory tract infections. Drugs. 2005;65(7):949-91. DOI: 10.2165/00003495-200565070-00004 PMID: 15892589

25. Hooper DC, Jacoby GA. Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance. Cold Spring Harb Perspect Med. 2016;6(9):a025320.

DOI: 10.1101/cshperspect.a025320 PMID: 27449972

26. Papillon J, Ménétret JF, Batisse C, Hélye R, Schultz P, Potier N, et al. Structural insight into negative DNA supercoiling by DNA gyrase, a bacterial type 2A DNA topoisomerase. Nucleic Acids Res. 2013;41(16):7815-27. DOI: 10.1093/nar/gkt560

PMID: 23804759

27. Schvartzman JB, Hernández P, Krimer DB, Dorier J, Stasiak A. Closing the DNA replication cycle: from simple circular molecules to supercoiled and knotted DNA catenanes. Nucleic Acids Res. 2019;47(14):7182-7198. DOI: 10.1093/nar/gkz586 PMID: 31276584

28. Deweese JE, Osheroff N. The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing. Nucleic Acids Res. 2009;37(3):738-48. DOI: 10.1093/nar/gkn937 PMID: 19042970

29. Podlesek Z, Žgur Bertok D. The DNA Damage Inducible SOS Response Is a Key Player in the Generation of Bacterial Persister Cells and Population Wide Tolerance. Front Microbiol. 2020;11:1785. DOI: 10.3389/fmicb.2020.01785

PMID: 32849403

30. Drlica K, Hiasa H, Kerns R, Malik M, Mustaev A, Zhao X. Quinolones: action and resistance updated. Curr Top Med Chem. 2009;9(11):981-98. DOI: 10.2174/156802609789630947

PMID: 19747119

31. Hooper DC, Jacoby GA. Mechanisms of drug resistance: quinolone resistance. Ann N Y Acad Sci. 2015;1354(1):12-31. DOI: 10.1111/nyas.12830 PMID: 26190223

32. Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis. 2000;31(Suppl 2):S24-8. DOI: 10.1086/314056 PMID: 10984324

33. Jacoby GA. Mechanisms of resistance to quinolones. Clin Infect Dis. 2005;41(Suppl 2):S120-6. DOI: 10.1086/428052

PMID: 15942878

34. Goñi-Urriza M, Arpin C, Capdepuy M, Dubois V, Caumette P, Quentin C. Type II topoisomerase quinolone resistance-determining regions of Aeromonas caviae, A. hydrophila, and A. sobria complexes and mutations associated with quinolone resistance. Antimicrob Agents Chemother. 2002;46(2):350-9. DOI: 10.1128/AAC.46.2.350-359.2002 PMID: 11796341

35. Laponogov I, Veselkov DA, Sohi MK, Pan XS, Achari A, Yang C, et al. Breakage-reunion domain of Streptococcus pneumoniae topoisomerase IV: crystal structure of a gram-positive quinolone target. PLoS One. 2007;2(3):e301.

DOI: 10.1371/journal.pone.0000301 PMID: 17375187

36. Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev. 2015;28(2):337-418. DOI: 10.1128/CMR.00117-14

PMID: 25788514

37. Jellen-Ritter AS, Kern WV. Enhanced expression of the multidrug efflux pumps AcrAB and AcrEF associated with insertion element transposition in Escherichia coli mutants Selected with a fluoroquinolone. Antimicrob Agents Chemother. 2001;45(5):1467-72. DOI: 10.1128/AAC.45.5.1467-1472.2001 PMID: 11302812

38. Alonso A, Martínez JL. Cloning and characterization of SmeDEF, a novel multidrug efflux pump from Stenotrophomonas maltophilia. Antimicrob Agents Chemother. 2000;44(11):3079-86. DOI: 10.1128/AAC.44.11.3079-3086.2000 PMID: 11036026

39. Arya SS, Sharma MM, Rookes JE, Cahill DM, Lenka SK. Vanilla modulates the activity of antibiotics and inhibits efflux pumps in drug-resistant Pseudomonas aeruginosa. Biologia. 2021;76:781-91. DOI: 10.2478/s11756-020-00617-5

40. Laudy AE. Non-antibiotics, Efflux Pumps and Drug Resistance of Gram-negative Rods. Pol J Microbiol. 2018;67(2):129-135. DOI: 10.21307/pjm-2018-017 PMID: 30015451

41. Costa SS, Sobkowiak B, Parreira R, Edgeworth JD, Viveiros M, Clark TG, et al. Genetic Diversity of norA, Coding for a Main Efflux Pump of Staphylococcus aureus. Front Genet. 2019;9:710. DOI: 10.3389/fgene.2018.00710 PMID: 30687388

42. Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria: an update. Drugs. 2009;69(12):1555-623. DOI: 10.2165/11317030-000000000-00000 PMID: 19678712

43. Karp BE, Campbell D, Chen JC, Folster JP, Friedman CR. Plasmid-mediated quinolone resistance in human non-typhoidal Salmonella infections: An emerging public health problem in the United States. Zoonoses Public Health. 2018;65(7):838-849. DOI: 10.1111/zph.12507 PMID: 30027554

44. Jacoby GA, Strahilevitz J, Hooper DC. Plasmid-mediated quinolone resistance. Microbiol Spectr. 2014;2(5):10.1128/microbiolspec.PLAS-0006-2013.

DOI: 10.1128/microbiolspec.PLAS-0006-2013 PMID: 25584197

45. Kim HB, Wang M, Park CH, Kim EC, Jacoby GA, Hooper DC. oqxAB encoding a multidrug efflux pump in human clinical isolates of Enterobacteriaceae. Antimicrob Agents Chemother. 2009;53(8):3582-4. DOI: 10.1128/AAC.01574-08

PMID: 19528276

46. Tao Y, Zhou K, Xie L, Xu Y, Han L, Ni Y, et al. Emerging coexistence of three PMQR genes on a multiple resistance plasmid with a new surrounding genetic structure of qnrS2 in E. coli in China. Antimicrob Resist Infect Control. 2020;9(1):52. DOI: 10.1186/s13756-020-00711-y PMID: 32293532

47. An XL, Chen QL, Zhu D, Zhu YG, Gillings MR, Su JQ. Impact of Wastewater Treatment on the Prevalence of Integrons and the Genetic Diversity of Integron Gene Cassettes. Appl Environ Microbiol. 2018;84(9):e02766-17. DOI: 10.1128/AEM.02766-17 PMID: 29475864

48. Schulz J, Kemper N, Hartung J, Janusch F, Mohring SAI, Hamscher G. Analysis of fluoroquinolones in dusts from intensive livestock farming and the co-occurrence of fluoroquinolone-resistant Escherichia coli. Sci Rep. 2019;9(1):5117. DOI: 10.1038/s41598-019-41528-z

PMID: 30914675

49. Gouvêa R, Dos Santos F, De Aquino M. Fluoroquinolones in industrial poultry production, bacterial resistance and food residues: a review. Brazilian Journal of Poultry Science. 2015;17:1-10. DOI: 10.1590/1516-635x17011-10

50. Martinez M, McDermott P, Walker R. Pharmacology of the fluoroquinolones: a perspective for the use in domestic animals. Vet J. 2006;172(1):10-28. DOI: 10.1016/j.tvjl.2005.07.010 PMID: 16154368

51. Ma Z, Lee S, Jeong KC. Mitigating Antibiotic Resistance at the Livestock-Environment Interface:A Review. J Microbiol Biotechnol. 2019;29(11):1683-1692.

DOI: 10.4014/jmb.1909.09030 PMID: 31693837

52. Capita R, Alonso-Calleja C. Antibiotic-resistant bacteria: a challenge for the food industry. Crit Rev Food Sci Nutr. 2013;53(1):11-48. DOI: 10.1080/10408398.2010.519837

PMID: 23035919

53. Moniri R, Dastehgoli K. Fluoroquinolone-resistant Escherichia coli isolated from healthy broilers with previous exposure to fluoroquinolones: Is there a link? Microbial ecology in health and disease. 2005;17(2):69-74. DOI: 10.3402/mehd.v17i2.7791

54. Humphrey TJ, Jørgensen F, Frost JA, Wadda H, Domingue G, Elviss NC, et al. Prevalence and subtypes of ciprofloxacin-resistant Campylobacter spp. in commercial poultry flocks before, during, and after treatment with fluoroquinolones. Antimicrob Agents Chemother. 2005;49(2):690-8.

DOI: 10.1128/AAC.49.2.690-698.2005 PMID: 15673753

55. Xu Y, Yu W, Ma Q, Zhou H. Occurrence of (fluoro)quinolones and (fluoro)quinolone resistance in soil receiving swine manure for 11 years. Sci Total Environ. 2015;530-531:191-197.

DOI: 10.1016/j.scitotenv.2015.04.046 PMID: 26042895

56. Hosain MZ, Kabir SML, Kamal MM. Antimicrobial uses for livestock production in developing countries. Vet World. 2021;14(1):210-221. DOI: 10.14202/vetworld.2021.210-221 PMID: 33642806

57. Goetting V, Lee KA, Tell LA. Pharmacokinetics of veterinary drugs in laying hens and residues in eggs: a review of the literature. J Vet Pharmacol Ther. 2011;34(6):521-56.

DOI: 10.1111/j.1365-2885.2011.01287.x PMID: 21679196

58. Wagner J, Gruz P, Kim SR, Yamada M, Matsui K, Fuchs RP, et al. The dinB gene encodes a novel E. coli DNA polymerase, DNA pol IV, involved in mutagenesis. Mol Cell. 1999;4(2):281-6.

DOI: 10.1016/s1097-2765(00)80376-7 PMID: 10488344

59. Butala M, Zgur-Bertok D, Busby SJ. The bacterial LexA transcriptional repressor. Cell Mol Life Sci. 2009;66(1):82-93. DOI: 10.1007/s00018-008-8378-6 PMID: 18726173

60. Aertsen A, Michiels CW. Mrr instigates the SOS response after high pressure stress in Escherichia coli. Mol Microbiol. 2005;58(5):1381-91. DOI: 10.1111/j.1365-2958.2005.04903.x PMID: 16313623

61. Waldor MK, Tschäpe H, Mekalanos JJ. A new type of conjugative transposon encodes resistance to sulfamethoxazole, trimethoprim, and streptomycin in Vibrio cholerae O139. J Bacteriol. 1996;178(14):4157-65. DOI: 10.1128/jb.178.14.4157-4165.1996 PMID: 8763944

62. Walker GC. The SOS response of Escherichia coli. Escherichia coli and Salmonella: cellular and molecular biology; 1996.

URL: https://ecosalgenes.frenoy.eu/pdf/810.pdf

63. Beaber JW, Hochhut B, Waldor MK. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature. 2004;427(6969):72-4. DOI: 10.1038/nature02241

PMID: 14688795

64. Rieu A, Briandet R, Habimana O, Garmyn D, Guzzo J, Piveteau P. Listeria monocytogenes EGD-e biofilms: no mushrooms but a network of knitted chains. Appl Environ Microbiol. 2008;74(14):4491-7. DOI: 10.1128/AEM.00255-08

PMID: 18502930

65. van der Veen S, Abee T. Dependence of continuous-flow biofilm formation by Listeria monocytogenes EGD-e on SOS response factor YneA. Appl Environ Microbiol. 2010;76(6):1992-5.

DOI: 10.1128/AEM.02680-09 PMID: 20097825

66. van der Veen S, van Schalkwijk S, Molenaar D, de Vos WM, Abee T, Wells-Bennik MHJ. The SOS response of Listeria monocytogenes is involved in stress resistance and mutagenesis. Microbiology (Reading). 2010;156(Pt 2):374-384.

DOI: 10.1099/mic.0.035196-0 PMID: 19892760

67. Andreozzi E, Gunther NW 4th, Reichenberger ER, Rotundo L, Cottrell BJ, Nuñez A, et al. Pch Genes Control Biofilm and Cell Adhesion in a Clinical Serotype O157:H7 Isolate. Front Microbiol. 2018;9:2829. DOI: 10.3389/fmicb.2018.02829

PMID: 30532745

68. Fornelos N, Browning DF, Butala M. The Use and Abuse of LexA by Mobile Genetic Elements. Trends Microbiol. 2016;24(5):391-401. DOI: 10.1016/j.tim.2016.02.009 PMID: 26970840

69. Zhang X, McDaniel AD, Wolf LE, Keusch GT, Waldor MK, Acheson DW. Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J Infect Dis. 2000;181(2):664-70. DOI: 10.1086/315239 PMID: 10669353

70. Ubeda C, Maiques E, Knecht E, Lasa I, Novick RP, Penadés JR. Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci. Mol Microbiol. 2005;56(3):836-44.

DOI: 10.1111/j.1365-2958.2005.04584.x PMID: 15819636