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Volume 10, Issue 2

Exploring the genetic basis of natural resistance to microcins Open Access

Abstract

produce an arsenal of antimicrobial compounds including microcins, ribosomally produced antimicrobial peptides showing diverse structures and mechanisms of action. Microcins target close relatives of the producing strain to promote its survival. Their narrow spectrum of antibacterial activity makes them a promising alternative to conventional antibiotics, as it should decrease the probability of resistance dissemination and collateral damage to the host’s microbiota. To assess the therapeutic potential of microcins, there is a need to understand the mechanisms of resistance to these molecules. In this study, we performed genomic analyses of the resistance to four microcins [microcin C, a nucleotide peptide; microcin J25, a lasso peptide; microcin B17, a linear azol(in)e-containing peptide; and microcin E492, a siderophore peptide] on a collection of 54 from three species: , and . A gene-targeted analysis revealed that about half of the microcin-resistant strains presented mutations of genes involved in the microcin mechanism of action, especially those involved in their uptake (, , and ). A genome-wide association study did not reveal any significant correlations, yet relevant genetic elements were associated with microcin resistance. These were involved in stress responses, biofilm formation, transport systems and acquisition of immunity genes. Additionally, microcin-resistant strains exhibited several mutations within genes involved in specific metabolic pathways, especially for and .

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antibiotics , Gram-negative bacteria , microcin and resistance
Funding
This study was supported by the:
  • International Development Research Centre (Award 109048-001)
    • Principle Award Recipient: IsmaïlFliss
  • Natural Sciences and Engineering Research Council of Canada (Award IRCPJ 499946-15)
    • Principle Award Recipient: IsmaïlFliss
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2024-02-26
2024-05-20
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References

  1. Michael Janda J, Sharon LA. The changing face of the family Enterobacteriaceae: new members, taxonomic issues, geographic expansion, and new diseases and disease syndromes. Clin Microbiol Rev 2021; 34:e00174-20 [View Article] [PubMed]
     [Google Scholar]
  2. Partridge SR. Resistance mechanisms in Enterobacteriaceae. Pathology 2015; 47:276–284 [View Article] [PubMed]
     [Google Scholar]
  3. Brink AJ. Epidemiology of carbapenem-resistant gram-negative infections globally. Curr Opin Infect Dis 2019; 32:609–616 [View Article] [PubMed]
     [Google Scholar]
  4. Zgurskaya HI, Löpez CA, Gnanakaran S. Permeability barrier of gram-negative cell envelopes and approaches to bypass it. ACS Infect Dis 2015; 1:512–522 [View Article] [PubMed]
     [Google Scholar]
  5. Koebnik R, Locher KP, Van Gelder P. Structure and function of bacterial outer membrane proteins: barrels in a nutshell. Mol Microbiol 2000; 37:239–253 [View Article] [PubMed]
     [Google Scholar]
  6. Fernández L, Hancock REW. Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev 2012; 25:661–681 [View Article] [PubMed]
     [Google Scholar]
  7. Choi U, Lee C-R. Distinct roles of outer membrane porins in antibiotic resistance and membrane integrity in Escherichia coli. Front Microbiol 2019; 10:953 [View Article] [PubMed]
     [Google Scholar]
  8. Li X-Z, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in gram-negative bacteria. Clin Microbiol Rev 2015; 28:337–418 [View Article] [PubMed]
     [Google Scholar]
  9. Patel G, Bonomo RA. “Stormy waters ahead”: global emergence of carbapenemases. Front Microbiol 2013; 4:48 [View Article] [PubMed]
     [Google Scholar]
  10. Baquero F, Lanza VF, Baquero M-R, Del Campo R, Bravo-Vázquez DA. Microcins in Enterobacteriaceae: peptide antimicrobials in the eco-active intestinal chemosphere. Front Microbiol 2019; 10:2261 [View Article] [PubMed]
     [Google Scholar]
  11. Telhig S, Ben Said L, Zirah S, Fliss I, Rebuffat S. Bacteriocins to thwart bacterial resistance in gram negative bacteria. Front Microbiol 2020; 11:586433 [View Article] [PubMed]
     [Google Scholar]
  12. Rebuffat S. Microcins in action: amazing defence strategies of Enterobacteria. Biochem Soc Trans 2012; 40:1456–1462 [View Article] [PubMed]
     [Google Scholar]
  13. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 2021; 19:55–71 [View Article] [PubMed]
     [Google Scholar]
  14. Kang K, Imamovic L, Misiakou M-A, Bornakke Sørensen M, Heshiki Y et al. Expansion and persistence of antibiotic-specific resistance genes following antibiotic treatment. Gut Microbes 2021; 13:1–19 [View Article] [PubMed]
     [Google Scholar]
  15. Soltani S, Hammami R, Cotter PD, Rebuffat S, Said LB et al. Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations. FEMS Microbiol Rev 2020; 45:fuaa039 [View Article] [PubMed]
     [Google Scholar]
  16. Cotter PD, Ross RP, Hill C. Bacteriocins - a viable alternative to antibiotics?. Nat Rev Microbiol 2013; 11:95–105 [View Article] [PubMed]
     [Google Scholar]
  17. Dalmasso G, Beyrouthy R, Brugiroux S, Ruppé E, Guillouard L et al. Genes mcr improve the intestinal fitness of pathogenic E. coli and balance their lifestyle to commensalism. Microbiome 2023; 11:12 [View Article] [PubMed]
     [Google Scholar]
  18. Telhig S, Ben Said L, Torres C, Rebuffat S, Zirah S et al. Evaluating the potential and synergetic effects of microcins against multidrug-resistant Enterobacteriaceae. Microbiol Spectr 2022; 10:e02752-21 [View Article] [PubMed]
     [Google Scholar]
  19. Metlitskaya A, Kazakov T, Kommer A, Pavlova O, Praetorius-Ibba M et al. Aspartyl-tRNA synthetase is the target of peptide nucleotide antibiotic microcin C. J Biol Chem 2006; 281:18033–18042 [View Article] [PubMed]
     [Google Scholar]
  20. Delgado MA, Rintoul MR, Farías RN, Salomón RA. Escherichia coli RNA polymerase is the target of the cyclopeptide antibiotic microcin J25. J Bacteriol 2001; 183:4543–4550 [View Article] [PubMed]
     [Google Scholar]
  21. Vizán JL, Hernández-Chico C, del Castillo I, Moreno F. The peptide antibiotic microcin B17 induces double-strand cleavage of DNA mediated by E. coli DNA gyrase. EMBO J 1991; 10:467–476 [View Article] [PubMed]
     [Google Scholar]
  22. Herrero M, Moreno F. Microcin B17 blocks DNA replication and induces the SOS system in Escherichia coli. J Gen Microbiol 1986; 132:393–402 [View Article] [PubMed]
     [Google Scholar]
  23. Collin F, Maxwell A. The microbial toxin microcin B17: prospects for the development of new antibacterial a gents. J Mol Biol 2019; 431:3400–3426 [View Article] [PubMed]
     [Google Scholar]
  24. Huang K, Zeng J, Liu X, Jiang T, Wang J. Structure of the mannose phosphotransferase system (man-PTS) complexed with microcin E492, a pore-forming bacteriocin. Cell Discov 2021; 7:20 [View Article] [PubMed]
     [Google Scholar]
  25. Destoumieux-Garzón D, Duquesne S, Peduzzi J, Goulard C, Desmadril M et al. The iron-siderophore transporter FhuA is the receptor for the antimicrobial peptide microcin J25: role of the microcin Val11-Pro16 beta-hairpin region in the recognition mechanism. Biochem J 2005; 389:869–876 [View Article] [PubMed]
     [Google Scholar]
  26. Delgado MA, Vincent PA, Farías RN, Salomón RA. YojI of Escherichia coli functions as a microcin J25 efflux pump. J Bacteriol 2005; 187:3465–3470 [View Article] [PubMed]
     [Google Scholar]
  27. Bountra K, Hagelueken G, Choudhury HG, Corradi V, El Omari K et al. Structural basis for antibacterial peptide self-immunity by the bacterial ABC transporter McjD. EMBO J 2017; 36:3062–3079 [View Article] [PubMed]
     [Google Scholar]
  28. Kazakov T, Kuznedelov K, Semenova E, Mukhamedyarov D, Datsenko KA et al. The RimL transacetylase provides resistance to translation inhibitor microcin C. J Bacteriol 2014; 196:3377–3385 [View Article] [PubMed]
     [Google Scholar]
  29. Smits SHJ, Schmitt L, Beis K. Self-immunity to antibacterial peptides by ABC transporters. FEBS Lett 2020; 594:3920–3942 [View Article] [PubMed]
     [Google Scholar]
  30. Severinov K, Nair SK. Microcin C: biosynthesis and mechanisms of bacterial resistance. Future Microbiol 2012; 7:281–289 [View Article] [PubMed]
     [Google Scholar]
  31. Novikova M, Kazakov T, Vondenhoff GH, Semenova E, Rozenski J et al. MccE provides resistance to protein synthesis inhibitor microcin C by acetylating the processed form of the antibiotic. J Biol Chem 2010; 285:12662–12669 [View Article] [PubMed]
     [Google Scholar]
  32. Tikhonov A, Kazakov T, Semenova E, Serebryakova M, Vondenhoff G et al. The mechanism of microcin C resistance provided by the MccF peptidase. J Biol Chem 2010; 285:37944–37952 [View Article] [PubMed]
     [Google Scholar]
  33. Vincent PA, Delgado MA, Farías RN, Salomón RA. Inhibition of Salmonella enterica serovars by microcin J25. FEMS Microbiol Lett 2004; 236:103–107 [View Article] [PubMed]
     [Google Scholar]
  34. Ben Said L, Emond-Rheault J-G, Soltani S, Telhig S, Zirah S et al. Phenomic and genomic approaches to studying the inhibition of multiresistant Salmonella enterica by microcin J25. Environ Microbiol 2020; 22:2907–2920 [View Article] [PubMed]
     [Google Scholar]
  35. Telhig S, Ben Said L, Torres C, Rebuffat S, Zirah S et al. Evaluating the potential and synergetic effects of microcins against multidrug-resistant Enterobacteriaceae. Microbiol Spectr 2021; 10:e02752-21 [View Article] [PubMed]
     [Google Scholar]
  36. Tritt A, Eisen JA, Facciotti MT, Darling AE. An integrated pipeline for de novo assembly of microbial genomes. PLoS One 2012; 7:e42304 [View Article] [PubMed]
     [Google Scholar]
  37. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article] [PubMed]
     [Google Scholar]
  38. Li L, Stoeckert CJ, Roos DS. OrthoMCL: identification of ortholog groups for eukaryotic genomes. Genome Res 2003; 13:2178–2189 [View Article] [PubMed]
     [Google Scholar]
  39. Contreras-Moreira B, Vinuesa P. Get_homologues, a versatile software package for scalable and robust microbial pangenome analysis. Appl Environ Microbiol 2013; 79:7696–7701 [View Article] [PubMed]
     [Google Scholar]
  40. Seemann T. snippy: fast bacterial variant calling from NGS reads; 2015 https://github.com/tseemann/snippy
  41. Price MN, Dehal PS, Arkin AP. FastTree 2--approximately maximum-likelihood trees for large alignments. PLoS One 2010; 5:e9490 [View Article] [PubMed]
     [Google Scholar]
  42. Seemann T. MLST github2015. n.d https://github.com/tseemann/mlst
  43. Jolley KA, Bray JE, Maiden MCJ. Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications. Wellcome Open Res 2018; 3:124 [View Article] [PubMed]
     [Google Scholar]
  44. Alcock BP, Raphenya AR, Lau TTY, Tsang KK, Bouchard M et al. CARD 2020: antibiotic resistome surveillance with the comprehensive antibiotic resistance database. Nucleic Acids Res 2019; 48:D517–D525 [View Article] [PubMed]
     [Google Scholar]
  45. Chen L, Zheng D, Liu B, Yang J, Jin Q. VFDB 2016: hierarchical and refined dataset for big data analysis--10 years on. Nucleic Acids Res 2015; 44:D694–D697 [View Article] [PubMed]
     [Google Scholar]
  46. Seemann T. Abricate; 2020 https://github.com/tseemann/abricate
  47. Brynildsrud O, Bohlin J, Scheffer L, Eldholm V. Rapid scoring of genes in microbial pan-genome-wide association studies with Scoary. Genome Biol 2016; 17:238 [View Article] [PubMed]
     [Google Scholar]
  48. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 2016; 32:2847–2849 [View Article] [PubMed]
     [Google Scholar]
  49. Levin-Reisman I, Ronin I, Gefen O, Braniss I, Shoresh N et al. Antibiotic tolerance facilitates the evolution of resistance. Science 2017; 355:826–830 [View Article] [PubMed]
     [Google Scholar]
  50. Arzanlou M, Chai WC, Venter H. Intrinsic, adaptive and acquired antimicrobial resistance in gram-negative bacteria. Essays Biochem 2017; 61:49–59 [View Article] [PubMed]
     [Google Scholar]
  51. Martínez JL, Coque TM, Baquero F. What is a resistance gene? Ranking risk in resistomes. Nat Rev Microbiol 2015; 13:116–123 [View Article] [PubMed]
     [Google Scholar]
  52. Goswami C, Fox S, Holden MTG, Connor M, Leanord A et al. Origin, maintenance and spread of antibiotic resistance genes within plasmids and chromosomes of bloodstream isolates of Escherichia coli. Microb Genom 2020; 6:e000353 [View Article] [PubMed]
     [Google Scholar]
  53. Delgado-Blas JF, Ovejero CM, David S, Montero N, Calero-Caceres W et al. Population genomics and antimicrobial resistance dynamics of Escherichia coli in wastewater and river environments. Commun Biol 2021; 4:457 [View Article] [PubMed]
     [Google Scholar]
  54. Pons A-M, Delalande F, Duarte M, Benoit S, Lanneluc I et al. Genetic analysis and complete primary structure of microcin L. Antimicrob Agents Chemother 2004; 48:505–513 [View Article] [PubMed]
     [Google Scholar]
  55. Micenková L, Bosák J, Štaudová B, Kohoutová D, Čejková D et al. Microcin determinants are associated with B2 phylogroup of human fecal Escherichia coli isolates. MicrobiologyOpen 2016; 5:490–498 [View Article] [PubMed]
     [Google Scholar]
  56. Pagès J-M, James CE, Winterhalter M. The porin and the permeating antibiotic: a selective diffusion barrier in gram-negative bacteria. Nat Rev Microbiol 2008; 6:893–903 [View Article] [PubMed]
     [Google Scholar]
  57. Gopal M, Elumalai S, Arumugam S, Durairajpandian V, Kannan MA et al. GyrA ser83 and ParC trp106 mutations in Salmonella enterica serovar typhi isolated from typhoid fever patients in tertiary care hospital. J Clin Diagn Res 2016; 10:DC14–DC18 [View Article] [PubMed]
     [Google Scholar]
  58. Reyna F, Huesca M, González V, Fuchs LY. Salmonella typhimurium gyrA mutations associated with fluoroquinolone resistance. Antimicrob Agents Chemother 1995; 39:1621–1623 [View Article] [PubMed]
     [Google Scholar]
  59. Masi M, Réfregiers M, Pos KM, Pagès J-M. Mechanisms of envelope permeability and antibiotic influx and efflux in gram-negative bacteria. Nat Microbiol 2017; 2:17001 [View Article] [PubMed]
     [Google Scholar]
  60. Gaillard-Gendron S, Vignon D, Cottenceau G, Graber M, Zorn N et al. Isolation, purification and partial amino acid sequence of a highly hydrophobic new microcin named microcin L produced by Escherichia coli. FEMS Microbiol Lett 2000; 193:95–98 [View Article] [PubMed]
     [Google Scholar]
  61. Card KJ, Thomas MD, Graves JL, Barrick JE, Lenski RE. Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment with Escherichia coli. Proc Natl Acad Sci U S A 2021; 118:e2016886118 [View Article] [PubMed]
     [Google Scholar]
  62. Piskunova J, Maisonneuve E, Germain E, Gerdes K, Severinov K. Peptide-nucleotide antibiotic microcin C is a potent inducer of stringent response and persistence in both sensitive and producing cells. Mol Microbiol 2017; 104:463–471 [View Article] [PubMed]
     [Google Scholar]
  63. Lewis K, Shan Y. Why tolerance invites resistance. Science 2017; 355:796 [View Article] [PubMed]
     [Google Scholar]
  64. Paradis-Bleau C, Kritikos G, Orlova K, Typas A, Bernhardt TG. A genome-wide screen for bacterial envelope biogenesis mutants identifies a novel factor involved in cell wall precursor metabolism. PLoS Genet 2014; 10:e1004056 [View Article] [PubMed]
     [Google Scholar]
  65. Herbst S, Lorkowski M, Sarenko O, Nguyen TKL, Jaenicke T et al. Transmembrane redox control and proteolysis of PdeC, a novel type of c-di-GMP phosphodiesterase. EMBO Rep 2018; 37:e97825 [View Article] [PubMed]
     [Google Scholar]
  66. Brown JM, Shaw KJ. A novel family of Escherichia coli toxin-antitoxin gene pairs. J Bacteriol 2003; 185:6600–6608 [View Article] [PubMed]
     [Google Scholar]
  67. Cheverton AM, Gollan B, Przydacz M, Wong CT, Mylona A et al. A Salmonella toxin promotes persister formation through acetylation of tRNA. Mol Cell 2016; 63:86–96 [View Article] [PubMed]
     [Google Scholar]
  68. Schifano JM, Cruz JW, Vvedenskaya IO, Edifor R, Ouyang M et al. tRNA is a new target for cleavage by a MazF toxin. Nucleic Acids Res 2016; 44:1256–1270 [View Article] [PubMed]
     [Google Scholar]
  69. Cheung-Lee WL, Parry ME, Jaramillo Cartagena A, Darst SA, Link AJ. Discovery and structure of the antimicrobial lasso peptide citrocin. J Biol Chem 2019; 294:6822–6830 [View Article] [PubMed]
     [Google Scholar]
  70. Xiu H, Wang M, Fage CD, He Y, Niu X et al. Discovery and characterization of rubrinodin provide clues into the evolution of lasso peptides. Biochemistry 2022; 61:595–607 [View Article] [PubMed]
     [Google Scholar]
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Exploring the genetic basis of natural resistance to microcins
M Gen 10, 001156 (2024); https://doi.org/10.1099/mgen.0.001156
/content/journal/mgen/10.1099/mgen.0.001156
/content/journal/mgen/10.1099/mgen.0.001156
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