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Volume 169, Issue 11

Anti-persister efficacy of colistin and meropenem against uropathogenic is dependent on environmental conditions Open Access

Abstract

Antibiotic persistence is a phenomenon observed when genetically susceptible cells survive long-term exposure to antibiotics. These ‘persisters’ are an intrinsic component of bacterial populations and stem from phenotypic heterogeneity. Persistence to antibiotics is a concern for public health globally, as it increases treatment duration and can contribute to treatment failure. Furthermore, there is a growing array of evidence that persistence is a ‘stepping-stone’ for the development of genetic antimicrobial resistance. Urinary tract infections (UTIs) are a major contributor to antibiotic consumption worldwide, and are known to be both persistent (i.e. affecting the host for a prolonged period) and recurring. Currently, in clinical settings, routine laboratory screening of pathogenic isolates does not determine the presence or the frequency of persister cells. Furthermore, the majority of research undertaken on antibiotic persistence has been done on lab-adapted bacterial strains. In the study presented here, we characterized antibiotic persisters in a panel of clinical uropathogenic isolates collected from hospitals in the UK and Australia. We found that a urine-pH mimicking environment not only induces higher levels of antibiotic persistence to meropenem and colistin than standard laboratory growth conditions, but also results in rapid development of transient colistin resistance, regardless of the genetic resistance profile of the isolate. Furthermore, we provide evidence for the presence of multiple virulence factors involved in stress resistance and biofilm formation in the genomes of these isolates, whose activities have been previously shown to contribute to the formation of persister cells.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antibiotic persistence , antimicrobial resistance , Escherichia coli and urinary tract infections
Funding
This study was supported by the:
  • Medical Research Council (Award MR/T028998/1)
    • Principle Award Recipient: SuzieHingley-Wilson
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2023-11-22
2024-05-19
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References

  1. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015; 13:269–284 [View Article] [PubMed]
     [Google Scholar]
  2. Clinical knowledge summary Urinary tract infection (lower). National Institute for Health and Care Excellence (NIHCE); 2021 https://cks.nice.org.uk/topics/urinary-tract-infection-lower-women/ accessed 21 September 2022
  3. Thornton HV, Hammond A, Hay AD. Urosepsis: a growing and preventable problem?. Br J Gen Pract 2018; 68:493–494 [View Article] [PubMed]
     [Google Scholar]
  4. Urinary tract infection (lower): antimicrobial prescribing National Institute for Health and Care Excellence (NIHCE); 2018 https://cks.nice.org.uk/topics/urinary-tract-infection-lower-women/ accessed 21 September 2022
  5. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990; 80:331–333 [View Article] [PubMed]
     [Google Scholar]
  6. Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B et al. Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol 2019; 17:441–448 [View Article] [PubMed]
     [Google Scholar]
  7. Bartell JA, Cameron DR, Mojsoska B, Haagensen JAJ, Pressler T et al. Bacterial persisters in long-term infection: emergence and fitness in a complex host environment. PLoS Pathog 2020; 16:e1009112 [View Article] [PubMed]
     [Google Scholar]
  8. McCune RM, Feldmann FM, Lambert HP, McDermott W. Microbial persistence. J Exp Med 1966; 123:445–468 [View Article] [PubMed]
     [Google Scholar]
  9. Hassan M, Butler M, Ranzoni A, Cooper M. Detection and quantification of Staphylococcus aureus heterogeneity to identify antibiotic-induced persistence. Access Microbiol 2019; 1: [View Article]
     [Google Scholar]
  10. Foxman B, Zhang L, Tallman P, Palin K, Rode C et al. Virulence characteristics of Escherichia coli causing first urinary tract infection predict risk of second infection. J Infect Dis 1995; 172:1536–1541 [View Article] [PubMed]
     [Google Scholar]
  11. Russo TA, Stapleton A, Wenderoth S, Hooton TM, Stamm WE. Chromosomal restriction fragment length polymorphism analysis of Escherichia coli strains causing recurrent urinary tract infections in young women. J Infect Dis 1995; 172:440–445 [View Article] [PubMed]
     [Google Scholar]
  12. Luo Y, Ma Y, Zhao Q, Wang L, Guo L et al. Similarity and divergence of phylogenies, antimicrobial susceptibilities, and virulence factor profiles of Escherichia coli isolates causing recurrent urinary tract infections that persist or result from reinfection. J Clin Microbiol 2012; 50:4002–4007 [View Article] [PubMed]
     [Google Scholar]
  13. Jarvis T, Chan L, Gottlieb T. Assessment and management of lower urinary tract infection in adults. Aust Prescr 2014; 37:7–9 [View Article]
     [Google Scholar]
  14. Australian report on antimicrobial use and resistance in human health (AURA) Australian Commission on Safety and Quality in Health Care; 2021 https://www.safetyandquality.gov.au/publications-and-resources/resource-library/aura-2021-fourth-australian-report-antimicrobial-use-and-resistance-human-health accessed 23 September 2023
  15. Tutone M, Bjerklund Johansen TE, Cai T, Mushtaq S, Livermore DM. Susceptibility and resistance to fosfomycin and other antimicrobial agents among pathogens causing lower urinary tract infections: findings of the SURF study. Int J Antimicrob Agents 2022; 59:106574 [View Article] [PubMed]
     [Google Scholar]
  16. Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis 2016; 3:15–21 [View Article] [PubMed]
     [Google Scholar]
  17. Andrade FF, Silva D, Rodrigues A, Pina-Vaz C. Colistin update on its mechanism of action and resistance, present and future challenges. Microorganisms 2020; 8:1716 [View Article] [PubMed]
     [Google Scholar]
  18. European Medicines Agency Categorisation of antibiotics used in animals promotes responsible use to protect public and animal health; 2020
  19. Windels EM, Michiels JE, Fauvart M, Wenseleers T, Van den Bergh B et al. Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates. ISME J 2019; 13:1239–1251 [View Article] [PubMed]
     [Google Scholar]
  20. Liu J, Gefen O, Ronin I, Bar-Meir M, Balaban NQ. Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science 2020; 367:200–204 [View Article] [PubMed]
     [Google Scholar]
  21. Van den Bergh B, Fauvart M, Michiels J. Formation, physiology, ecology, evolution and clinical importance of bacterial persisters. FEMS Microbiol Rev 2017; 41:219–251 [View Article] [PubMed]
     [Google Scholar]
  22. Nunez-Garcia J, AbuOun M, Storey N, Brouwer MS, Delgado-Blas JF et al. Harmonisation of in-silico next-generation sequencing based methods for diagnostics and surveillance. Sci Rep 2022; 12:14372 [View Article] [PubMed]
     [Google Scholar]
  23. Ognenovska S, Mukerjee C, Sanderson-Smith M, Moore KH, Mansfield KJ. Virulence mechanisms of common uropathogens and their intracellular localisation within urothelial cells. Pathogens 2022; 11:926 [View Article] [PubMed]
     [Google Scholar]
  24. Harms A, Fino C, Sørensen MA, Semsey S, Gerdes K. Prophages and growth dynamics confound experimental results with antibiotic-tolerant persister cells. mBio 2017; 8:e01964-17 [View Article] [PubMed]
     [Google Scholar]
  25. Miles AA, Misra SS, Irwin JO. The estimation of the bactericidal power of the blood. Epidemiol Infect 1938; 38:732–749 [View Article] [PubMed]
     [Google Scholar]
  26. EUCAST Breakpoint tables for interpretation of MICs and zone diameters Version 9.0. 2019. Breakpoint tables for interpretation of MICs and zone diameters Version 9.0; 2019 https://www.safetyandquality.gov.au/our-work/healthcare-variation/fourth-atlas-2021/chronic-disease-and-infection-potentially-preventable-hospitalisations/24-kidney-infections-and-urinary-tract-infections
  27. Prjibelski A, Antipov D, Meleshko D, Lapidus A, Korobeynikov A. Using SPAdes De Novo assembler. Curr Protoc Bioinformatics 2020; 70:e102 [View Article] [PubMed]
     [Google Scholar]
  28. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article] [PubMed]
     [Google Scholar]
  29. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2012; 41:D590–D596 [View Article] [PubMed]
     [Google Scholar]
  30. Feldgarden M, Brover V, Gonzalez-Escalona N, Frye JG, Haendiges J et al. AMRFinderPlus and the reference gene catalog facilitate examination of the genomic links among antimicrobial resistance, stress response, and virulence. Sci Rep 2021; 11:12728 [View Article] [PubMed]
     [Google Scholar]
  31. Worcester EM, Bergsland KJ, Gillen DL, Coe FL. Mechanism for higher urine pH in normal women compared with men. Am J Physiol Renal Physiol 2018; 314:F623–F629 [View Article] [PubMed]
     [Google Scholar]
  32. Zarkan A, Caño-Muñiz S, Zhu J, Al Nahas K, Cama J et al. Indole pulse signalling regulates the cytoplasmic pH of E. coli in a memory-like manner. Sci Rep 2019; 9:3868 [View Article] [PubMed]
     [Google Scholar]
  33. Sánchez-Clemente R, Igeño MI, Población AG, Guijo MI, Merchán F et al. Study of pH changes in media during bacterial growth of several environmental strains. In Environment, Green Technology, and Engineering International Conference 2018 [View Article]
     [Google Scholar]
  34. Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268–281 [View Article] [PubMed]
     [Google Scholar]
  35. Lee J, Page R, García-Contreras R, Palermino J-M, Zhang X-S et al. Structure and function of the Escherichia coli protein YmgB: a protein critical for biofilm formation and acid-resistance. J Mol Biol 2007; 373:11–26 [View Article] [PubMed]
     [Google Scholar]
  36. Chaturvedi KS, Hung CS, Giblin DE, Urushidani S, Austin AM et al. Cupric yersiniabactin is a virulence-associated superoxide dismutase mimic. ACS Chem Biol 2014; 9:551–561 [View Article] [PubMed]
     [Google Scholar]
  37. Hingley-Wilson SM, Ma N, Hu Y, Casey R, Bramming A et al. Loss of phenotypic inheritance associated with ydcI mutation leads to increased frequency of small, slow persisters in Escherichia coli. Proc Natl Acad Sci U S A 2020; 117:4152–4157 [View Article] [PubMed]
     [Google Scholar]
  38. Balaban NQ, Merrin J, Chait R, Kowalik L, Leibler S. Bacterial persistence as a phenotypic switch. Science 2004; 305:1622–1625 [View Article] [PubMed]
     [Google Scholar]
  39. Moyed HS, Bertrand KP. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 1983; 155:768–775 [View Article] [PubMed]
     [Google Scholar]
  40. Korch SB, Henderson TA, Hill TM. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol Microbiol 2003; 50:1199–1213 [View Article] [PubMed]
     [Google Scholar]
  41. Cox CE, Holloway WJ, Geckler RW. A multicenter comparative study of meropenem and imipenem/cilastatin in the treatment of complicated urinary tract infections in hospitalized patients. Clin Infect Dis 1995; 21:86–92 [View Article] [PubMed]
     [Google Scholar]
  42. Haugan MS, Hertz FB, Charbon G, Sahin B, Løbner-Olesen A et al. Growth rate of Escherichia coli during human urinary tract infection: implications for antibiotic effect. Antibiotics 2019; 8:92 [View Article] [PubMed]
     [Google Scholar]
  43. Lai H-C, Chang S-N, Lin H-C, Hsu Y-L, Wei H-M et al. Association between urine pH and common uropathogens in children with urinary tract infections. J Microbiol Immunol Infect 2021; 54:290–298 [View Article] [PubMed]
     [Google Scholar]
  44. Heimer SR, Welch RA, Perna NT, Pósfai G, Evans PS et al. Urease of enterohemorrhagic Escherichia Coli: evidence for regulation by fur and a trans -acting factor. Infect Immun 20021027–1031
     [Google Scholar]
  45. Domínguez-Bello MG, Reyes N, Teppa-Garrán A, Romero R. Interference of Pseudomonas strains in the identification of Helicobacter pylori. J Clin Microbiol 2000; 38:937 [View Article] [PubMed]
     [Google Scholar]
  46. Krakkattu J, Mohan A, James E, Kumar A. Effectiveness and safety of colistin in multi drug resistant urinary tract infections. J Appl Pharm Sci 2017
     [Google Scholar]
  47. Sorlí L, Luque S, Li J, Campillo N, Danés M et al. Colistin for the treatment of urinary tract infections caused by extremely drug-resistant Pseudomonas aeruginosa: dose is critical. J Infect 2019; 79:253–261 [View Article] [PubMed]
     [Google Scholar]
  48. Anderl JN, Zahller J, Roe F, Stewart PS. Role of nutrient limitation and stationary-phase existence in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin. Antimicrob Agents Chemother 2003; 47:1251–1256 [View Article] [PubMed]
     [Google Scholar]
  49. Amato SM, Brynildsen MP. Nutrient transitions are a source of persisters in Escherichia coli biofilms. PLoS One 2014; 9:e93110 [View Article] [PubMed]
     [Google Scholar]
  50. Nguyen D, Joshi-Datar A, Lepine F, Bauerle E, Olakanmi O et al. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 2011; 334:982–986 [View Article] [PubMed]
     [Google Scholar]
  51. Nishino K, Yamasaki S, Nakashima R, Zwama M, Hayashi-Nishino M. Function and inhibitory mechanisms of multidrug efflux pumps. Front Microbiol 2021; 12:737288 [View Article] [PubMed]
     [Google Scholar]
  52. Pugh HL, Connor C, Siasat P, McNally A, Blair JMA. E. coli ST11 (O157:H7) does not encode a functional AcrF efflux pump. Microbiology 2023; 169:001324 [View Article] [PubMed]
     [Google Scholar]
  53. Pu Y, Zhao Z, Li Y, Zou J, Ma Q et al. Enhanced efflux activity facilitates drug tolerance in dormant bacterial cells. Mol Cell 2016; 62:284–294 [View Article] [PubMed]
     [Google Scholar]
  54. Chetri S, Dolley A, Bhowmik D, Chanda DD, Chakravarty A et al. Transcriptional response of AcrEF-TolC against fluoroquinolone and carbapenem in Escherichia coli of clinical origin. Indian J Med Microbiol 2018; 36:537–540 [View Article] [PubMed]
     [Google Scholar]
  55. Semanjski M, Germain E, Bratl K, Kiessling A, Gerdes K et al. The kinases HipA and HipA7 phosphorylate different substrate pools in Escherichia coli to promote multidrug tolerance. Sci Signal 2018; 11:eaat5750 [View Article] [PubMed]
     [Google Scholar]
  56. Fux CA, Wilson S, Stoodley P. Detachment characteristics and oxacillin resistance of Staphyloccocus aureus biofilm emboli in an in vitro catheter infection model. J Bacteriol 2004; 186:4486–4491 [View Article] [PubMed]
     [Google Scholar]
  57. Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 2007; 130:797–810 [View Article] [PubMed]
     [Google Scholar]
  58. Cirz RT, Jones MB, Gingles NA, Minogue TD, Jarrahi B et al. Complete and SOS-mediated response of Staphylococcus aureus to the antibiotic ciprofloxacin. J Bacteriol 2007; 189:531–539 [View Article] [PubMed]
     [Google Scholar]
  59. Sebastian J, Swaminath S, Nair RR, Jakkala K, Pradhan A et al. De Novo emergence of genetically resistant mutants of Mycobacterium tuberculosis from the persistence phase cells formed against antituberculosis drugs In Vitro. Antimicrob Agents Chemother 2017; 61:e01343-16 [View Article] [PubMed]
     [Google Scholar]
  60. Zwanzig M. The ecology of plasmid-coded antibiotic resistance: a basic framework for experimental research and modeling. Comput Struct Biotechnol J 2021; 19:586–599 [View Article] [PubMed]
     [Google Scholar]
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Anti-persister efficacy of colistin and meropenem against uropathogenic Escherichia coli is dependent on environmental conditions
Microbiology 169, 001403 (2023); https://doi.org/10.1099/mic.0.001403
/content/journal/micro/10.1099/mic.0.001403
/content/journal/micro/10.1099/mic.0.001403
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