Skip to content
1887

Microbial Genomics logo Microbial Genomics

Volume 11, Issue 1

The dominant lineage of an emerging pathogen harbours contact-dependent inhibition systems Open Access

Abstract

Bacteria from the complex (Smc) are important multidrug-resistant pathogens that cause a broad range of infections. Smc is genomically diverse and has been classified into 23 lineages. Lineage Sm6 is the most common among sequenced strains, but it is unclear why this lineage has evolved to be dominant. Antagonistic interactions can significantly affect the evolution of bacterial populations. These interactions may be mediated by secreted contact-dependent proteins, which allow inhibitor cells to intoxicate adjacent target bacteria. Contact-dependent inhibition (CDI) requires three proteins: CdiA, CdiB and CdiI. CdiA is a large, filamentous protein exported to the surface of inhibitor cells through the pore-like CdiB. The CdiA C-terminal domain (CdiA-CT) is toxic when delivered into target cells of the same species or genus. CdiI immunity proteins neutralize the toxicity of cognate CdiA-CT toxins. We found that all complete Smc genomes from the Sm6 lineage harbour at least one CDI locus. By contrast, less than a quarter of strains from other lineages have CDI genes. Smc CdiA-CT domains are diverse and have a broad range of predicted functions. Most Sm6 strains harbour non-cognate genes predicted to provide protection against foreign toxins from other strains. Finally, we demonstrated that an Smc CdiA-CT toxin has antibacterial properties and is neutralized by its cognate CdiI.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): contact-dependent inhibition , emerging pathogen and Stenotrophomonas maltophilia
Funding
This study was supported by the:
  • Office of Extramural Research, National Institutes of Health (Award IRACDA)
    • Principal Award Recipient: CristianV. Crisan
  • Office of Extramural Research, National Institutes of Health (Award R21AI148847)
    • Principal Award Recipient: JoannaB. Goldberg
  • Cystic Fibrosis Foundation (Award CRISAN22F0)
    • Principal Award Recipient: CristianV. Crisan
  • Cystic Fibrosis Foundation (Award WHITEL20A0)
    • Principal Award Recipient: JoannaB. Goldberg
  • Cystic Fibrosis Foundation (Award GOLDBE19I0)
    • Principal Award Recipient: JoannaB. Goldberg
© 2025 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Loading

Article metrics loading...

/content/journal/mgen/10.1099/mgen.0.001332
2025-01-24
2026-02-11

Metrics

Loading full text...

Full text loading...

/deliver/fulltext/mgen/11/1/mgen001332.html?itemId=/content/journal/mgen/10.1099/mgen.0.001332&mimeType=html&fmt=ahah

References

  1. Brooke JS. Advances in the microbiology of Stenotrophomonas maltophilia. Clin Microbiol Rev 2021; 34:e0003019 [View Article] [PubMed]
     [Google Scholar]
  2. Looney WJ, Narita M, Mühlemann K. Stenotrophomonas maltophilia: an emerging opportunist human pathogen. Lancet Infect Dis 2009; 9:312–323 [View Article] [PubMed]
     [Google Scholar]
  3. Rémi J, Loesch-Biffar AM, Mehrkens J, Thon N, Seelos K et al. Stenotrophomonas maltophilia brain abscesses after implantation of motor cortex stimulator. J Neurol Sci 2019; 400:32–33 [View Article] [PubMed]
     [Google Scholar]
  4. Fujiwara S, Gokon Y. Migratory cellulitis: Stenotrophomonas maltophilia infection of the skin. BMJ Case Rep 2021; 14:e239601 [View Article] [PubMed]
     [Google Scholar]
  5. Cai B, Tillotson G, Benjumea D, Callahan P, Echols R. The burden of bloodstream infections due to Stenotrophomonas maltophilia in the United States: a large, retrospective database study. Open Forum Infect Dis 2020; 7:ofaa141 [View Article] [PubMed]
     [Google Scholar]
  6. Kim EJ, Kim YC, Ahn JY, Jeong SJ, Ku NS et al. Risk factors for mortality in patients with Stenotrophomonas maltophilia bacteremia and clinical impact of quinolone-resistant strains. BMC Infect Dis 2019; 19:754 [View Article] [PubMed]
     [Google Scholar]
  7. Safdar A, Rolston KV. Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis 2007; 45:1602–1609 [View Article] [PubMed]
     [Google Scholar]
  8. Waters V, Yau Y, Prasad S, Lu A, Atenafu E et al. Stenotrophomonas maltophilia in cystic fibrosis. Am J Respir Crit Care Med 2011; 183:635–640
     [Google Scholar]
  9. Waters V, Atenafu EG, Lu A, Yau Y, Tullis E et al. Chronic Stenotrophomonas maltophilia infection and mortality or lung transplantation in cystic fibrosis patients. J Cyst Fibros 2013; 12:482–486 [View Article] [PubMed]
     [Google Scholar]
  10. Rønn C, Kamstrup P, Eklöf J, Toennesen LL, Boel JB et al. Mortality and exacerbations associated with Stenotrophomonas maltophilia in chronic obstructive pulmonary disease. A regional cohort study of 22,689 outpatients. Respir Res 2023; 24:232 [View Article] [PubMed]
     [Google Scholar]
  11. Langford BJ, So M, Simeonova M, Leung V, Lo J et al. Antimicrobial resistance in patients with COVID-19: a systematic review and meta-analysis. Lancet Microbe 2023; 4:e179–e191 [View Article] [PubMed]
     [Google Scholar]
  12. Scalia G, Ponzo G, Giuffrida M, Patanè D, Riso MF et al. Stenotrophomonas maltophilia-associated odontogenic cerebral abscess in an immunocompetent patient: a case report. Clin Case Rep 2024; 12:e9168 [View Article] [PubMed]
     [Google Scholar]
  13. Sánchez MB. Antibiotic resistance in the opportunistic pathogen Stenotrophomonas maltophilia. Front Microbiol 2015; 6:658 [View Article] [PubMed]
     [Google Scholar]
  14. Rello J, Kalwaje Eshwara V, Lagunes L, Alves J, Wunderink RG et al. A global priority list of the TOp TEn resistant Microorganisms (TOTEM) study at intensive care: a prioritization exercise based on multi-criteria decision analysis. Eur J Clin Microbiol Infect Dis 2019; 38:319–323 [View Article]
     [Google Scholar]
  15. Gröschel MI, Meehan CJ, Barilar I, Diricks M, Gonzaga A et al. The phylogenetic landscape and nosocomial spread of the multidrug-resistant opportunist Stenotrophomonas maltophilia. Nat Commun 2020; 11:2044 [View Article] [PubMed]
     [Google Scholar]
  16. Peterson SB, Bertolli SK, Mougous JD. The central role of interbacterial antagonism in bacterial life. Curr Biol 2020; 30:R1203–R1214 [View Article] [PubMed]
     [Google Scholar]
  17. Booth SC, Smith WPJ, Foster KR. The evolution of short- and long-range weapons for bacterial competition. Nat Ecol Evol 2023; 7:2080–2091 [View Article] [PubMed]
     [Google Scholar]
  18. Foster KR, Bell T. Competition, not cooperation, dominates interactions among culturable microbial species. Curr Biol 2012; 22:1845–1850 [View Article] [PubMed]
     [Google Scholar]
  19. McNally L, Bernardy E, Thomas J, Kalziqi A, Pentz J et al. Killing by Type VI secretion drives genetic phase separation and correlates with increased cooperation. Nat Commun 2017; 8:14371 [View Article] [PubMed]
     [Google Scholar]
  20. Russel J, Røder HL, Madsen JS, Burmølle M, Sørensen SJ. Antagonism correlates with metabolic similarity in diverse bacteria. Proc Natl Acad Sci U S A 2017; 114:10684–10688 [View Article] [PubMed]
     [Google Scholar]
  21. Freilich S, Zarecki R, Eilam O, Segal ES, Henry CS et al. Competitive and cooperative metabolic interactions in bacterial communities. Nat Commun 2011; 2:589 [View Article] [PubMed]
     [Google Scholar]
  22. Hibbing ME, Fuqua C, Parsek MR, Peterson SB. Bacterial competition: surviving and thriving in the microbial jungle. Nat Rev Microbiol 2010; 8:15–25 [View Article] [PubMed]
     [Google Scholar]
  23. Steinbach G, Crisan C, Ng SL, Hammer BK, Yunker PJ. Accumulation of dead cells from contact killing facilitates coexistence in bacterial biofilms. J R Soc Interface 2020; 17:20200486 [View Article] [PubMed]
     [Google Scholar]
  24. Niehus R, Oliveira NM, Li A, Fletcher AG, Foster KR. 2021; The evolution of strategy in bacterial warfare via the regulation of bacteriocins and antibiotics. eLife 10: [View Article]
     [Google Scholar]
  25. Crisan CV, Goldberg JB. Antibacterial contact-dependent proteins secreted by Gram-negative cystic fibrosis respiratory pathogens. Trends Microbiol 2022; 30:986–996 [View Article] [PubMed]
     [Google Scholar]
  26. Crisan CV, Chandrashekar H, Everly C, Steinbach G, Hill SE et al. A new contact killing toxin permeabilizes cells and belongs to a broadly distributed protein family. mSphere 2021; 6: [View Article]
     [Google Scholar]
  27. Crisan CV, Chande AT, Williams K, Raghuram V, Rishishwar L et al. Analysis of Vibrio cholerae genomes identifies new type VI secretion system gene clusters. Genome Biol 2019; 20:163 [View Article] [PubMed]
     [Google Scholar]
  28. Ruhe ZC, Low DA, Hayes CS. Bacterial contact-dependent growth inhibition. Trends Microbiol 2013; 21:230–237 [View Article] [PubMed]
     [Google Scholar]
  29. Aoki SK, Pamma R, Hernday AD, Bickham JE, Braaten BA et al. Contact-dependent inhibition of growth in Escherichia coli. Science 2005; 309:1245–1248 [View Article] [PubMed]
     [Google Scholar]
  30. Hayes CS, Koskiniemi S, Ruhe ZC, Poole SJ, Low DA. Mechanisms and biological roles of contact-dependent growth inhibition systems. Cold Spring Harb Perspect Med 2014; 4:a010025 [View Article] [PubMed]
     [Google Scholar]
  31. Allen JP, Hauser AR. Diversity of contact-dependent growth inhibition systems of Pseudomonas aeruginosa. J Bacteriol 2019; 201: [View Article]
     [Google Scholar]
  32. Tatarenkov A, Muñoz-Gutiérrez I, Vargas I, Behnsen J, Mota-Bravo L. Pangenome analysis reveals novel contact-dependent growth inhibition system and phenazine biosynthesis operons in Proteus mirabilis BL95 that are located in an integrative and conjugative element. Microorganisms 2024; 12:1321 [View Article] [PubMed]
     [Google Scholar]
  33. De Gregorio E, Zarrilli R, Di Nocera PP. Contact-dependent growth inhibition systems in Acinetobacter. Sci Rep 2019; 9:154 [View Article] [PubMed]
     [Google Scholar]
  34. Ruhe ZC, Wallace AB, Low DA, Hayes CS. Receptor polymorphism restricts contact-dependent growth inhibition to members of the same species. mBio 2013; 4: [View Article]
     [Google Scholar]
  35. Myers-Morales T, Oates AE, Byrd MS, Garcia EC. Burkholderia cepacia complex contact-dependent growth inhibition systems mediate interbacterial competition. J Bacteriol 2019; 201:e00012-19 [View Article] [PubMed]
     [Google Scholar]
  36. Aoki SK, Diner EJ, de Roodenbeke C t, Burgess BR, Poole SJ et al. A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria. Nature 2010; 468:439–442 [View Article]
     [Google Scholar]
  37. Nikolakakis K, Amber S, Wilbur JS, Diner EJ, Aoki SK et al. The toxin/immunity network of Burkholderia pseudomallei contact-dependent growth inhibition (CDI) systems. Mol Microbiol 2012; 84:516–529 [View Article] [PubMed]
     [Google Scholar]
  38. Aoki SK, Poole SJ, Hayes CS, Low DA. Toxin on a stick. Virulence 2011; 2:356–359 [View Article]
     [Google Scholar]
  39. Beck CM, Willett JLE, Cunningham DA, Kim JJ, Low DA et al. CdiA effectors from uropathogenic Escherichia coli use heterotrimeric osmoporins as receptors to recognize target bacteria. PLoS Pathog 2016; 12:e1005925 [View Article] [PubMed]
     [Google Scholar]
  40. Ruhe ZC, Nguyen JY, Xiong J, Koskiniemi S, Beck CM et al. CdiA effectors use modular receptor-binding domains to recognize target bacteria. mBio 2017; 8:1–16 [View Article] [PubMed]
     [Google Scholar]
  41. Poole SJ, Diner EJ, Aoki SK, Braaten BA, t’Kint de Roodenbeke C et al. Identification of functional toxin/immunity genes linked to contact-dependent growth inhibition (CDI) and rearrangement hotspot (Rhs) systems. PLoS Genet 2011; 7:e1002217 [View Article] [PubMed]
     [Google Scholar]
  42. Jain C, Rodriguez-R LM, Phillippy AM, Konstantinidis KT, Aluru S. High throughput ANI analysis of 90K prokaryotic genomes reveals clear species boundaries. Nat Commun 2018; 9:5114 [View Article] [PubMed]
     [Google Scholar]
  43. Letunic I, Bork P. Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation. Nucleic Acids Res 2021; 49:W293–W296 [View Article] [PubMed]
     [Google Scholar]
  44. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article] [PubMed]
     [Google Scholar]
  45. Willett JLE, Gucinski GC, Fatherree JP, Low DA, Hayes CS. Contact-dependent growth inhibition toxins exploit multiple independent cell-entry pathways. Proc Natl Acad Sci USA 2015; 112:11341–11346 [View Article]
     [Google Scholar]
  46. Paysan-Lafosse T, Blum M, Chuguransky S, Grego T, Pinto BL et al. InterPro in 2022. Nucleic Acids Res 2023; 51:D418–D427 [View Article] [PubMed]
     [Google Scholar]
  47. Marchler-Bauer A, Derbyshire MK, Gonzales NR, Lu S, Chitsaz F et al. CDD: NCBI’s conserved domain database. Nucleic Acids Res 2015; 43:D222–6 [View Article] [PubMed]
     [Google Scholar]
  48. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015; 10:845–858 [View Article] [PubMed]
     [Google Scholar]
  49. Gabler F, Nam S-Z, Till S, Mirdita M, Steinegger M et al. Protein sequence analysis using the MPI bioinformatics toolkit. Curr Protoc Bioinformatics 2020; 72:e108 [View Article] [PubMed]
     [Google Scholar]
  50. Sievers F, Higgins DG. Clustal Omega for making accurate alignments of many protein sequences. Protein Sci 2018; 27:135–145 [View Article] [PubMed]
     [Google Scholar]
  51. Babicki S, Arndt D, Marcu A, Liang Y, Grant JR et al. Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res 2016; 44:W147–53 [View Article] [PubMed]
     [Google Scholar]
  52. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004; 32:1792–1797 [View Article] [PubMed]
     [Google Scholar]
  53. Crisan CV, Pettis ML, Goldberg JB. Antibacterial potential of Stenotrophomonas maltophilia complex cystic fibrosis isolates. mSphere 2024; 9:e0033524 [View Article] [PubMed]
     [Google Scholar]
  54. Johnson PM, Gucinski GC, Garza-Sánchez F, Wong T, Hung L-W et al. Functional diversity of cytotoxic tRNase/immunity protein complexes from Burkholderia pseudomallei. J Biol Chem 2016; 291:19387–19400 [View Article] [PubMed]
     [Google Scholar]
  55. Beck CM, Morse RP, Cunningham DA, Iniguez A, Low DA et al. CdiA from Enterobacter cloacae delivers a toxic ribosomal RNase into target bacteria. Structure 2014; 22:707–718 [View Article] [PubMed]
     [Google Scholar]
  56. Batot G, Michalska K, Ekberg G, Irimpan EM, Joachimiak G et al. The CDI toxin of Yersinia kristensenii is a novel bacterial member of the RNase a superfamily. Nucleic Acids Res 2017; 45:5013–5025 [View Article] [PubMed]
     [Google Scholar]
  57. Zhang D, de Souza RF, Anantharaman V, Iyer LM, Aravind L. Polymorphic toxin systems: comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics. Biol Direct 2012; 7:18 [View Article] [PubMed]
     [Google Scholar]
  58. Webb JS, Nikolakakis KC, Willett JLE, Aoki SK, Hayes CS et al. Delivery of CdiA nuclease toxins into target cells during contact-dependent growth inhibition. PLoS One 2013; 8:e57609 [View Article] [PubMed]
     [Google Scholar]
  59. Graille M, Mora L, Buckingham RH, van Tilbeurgh H, de Zamaroczy M. Structural inhibition of the colicin D tRNase by the tRNA-mimicking immunity protein. EMBO J 2004; 23:1474–1482 [View Article] [PubMed]
     [Google Scholar]
  60. Nas MY, White RC, DuMont AL, Lopez AE, Cianciotto NP. Stenotrophomonas maltophilia encodes a VirB/VirD4 Type IV secretion system that modulates apoptosis in human cells and promotes competition against heterologous bacteria, including Pseudomonas aeruginosa. Infect Immun 2019; 87:e00457-19 [View Article] [PubMed]
     [Google Scholar]
  61. Nas MY, Gabell J, Cianciotto NP. Effectors of the Stenotrophomonas maltophilia type IV secretion system mediate killing of clinical isolates of Pseudomonas aeruginosa. mBio 2021; 12:e0150221 [View Article] [PubMed]
     [Google Scholar]
  62. Bayer-Santos E, Cenens W, Matsuyama BY, Oka GU, Di Sessa G et al. The opportunistic pathogen Stenotrophomonas maltophilia utilizes a type IV secretion system for interbacterial killing. PLoS Pathog 2019; 15:e1007651 [View Article] [PubMed]
     [Google Scholar]
  63. Crisan CV, Van Tyne D, Goldberg JB. The type VI secretion system of the emerging pathogen Stenotrophomonas maltophilia complex has antibacterial properties. mSphere 2023; 8:e0058423 [View Article] [PubMed]
     [Google Scholar]
  64. Cobe BL, Dey S, Minasov G, Inniss N, Satchell KJF et al. Bactericidal effectors of the Stenotrophomonas maltophilia type IV secretion system: functional definition of the nuclease TfdA and structural determination of TfcB. mBio 2024; 15:e0119824 [View Article] [PubMed]
     [Google Scholar]
  65. Gucinski GC, Michalska K, Garza-Sánchez F, Eschenfeldt WH, Stols L et al. Convergent evolution of the Barnase/EndoU/Colicin/RelE (BECR) fold in antibacterial tRNase toxins. Structure 2019; 27:1660–1674 [View Article] [PubMed]
     [Google Scholar]
  66. Garcia EC, Perault AI, Marlatt SA, Cotter PA. Interbacterial signaling via Burkholderia contact-dependent growth inhibition system proteins. Proc Natl Acad Sci U S A 2016; 113:8296–8301 [View Article] [PubMed]
     [Google Scholar]
  67. Roussin M, Rabarioelina S, Cluzeau L, Cayron J, Lesterlin C et al. Identification of a contact-dependent growth inhibition (cdi) system that reduces biofilm formation and host cell adhesion of Acinetobacter baumannii DSM30011 strain. Front Microbiol 2019; 10:2450 [View Article] [PubMed]
     [Google Scholar]
  68. Mercy C, Ize B, Salcedo SP, de Bentzmann S, Bigot S. Functional characterization of Pseudomonas contact dependent growth inhibition (CDI) Systems. PLoS One 2016; 11:e0147435 [View Article] [PubMed]
     [Google Scholar]
  69. Ruhe ZC, Townsley L, Wallace AB, King A, Van der Woude MW et al. CdiA promotes receptor-independent intercellular adhesion. Mol Microbiol 2015; 98:175–192 [View Article] [PubMed]
     [Google Scholar]
  70. Allen JP, Ozer EA, Minasov G, Shuvalova L, Kiryukhina O et al. A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant. Proc Natl Acad Sci USA 2020; 117:6811–6821 [View Article]
     [Google Scholar]
  71. Elery ZK, Myers-Morales T, Phillips ED, Garcia EC. Relaxed specificity of BcpB transporters mediates interactions between Burkholderia cepacia complex contact-dependent growth inhibition systems. mSphere 2023; 8:e0030323 [View Article] [PubMed]
     [Google Scholar]
  72. Madeira F, Madhusoodanan N, Lee J, Eusebi A, Niewielska A et al. The EMBL-EBI Job Dispatcher sequence analysis tools framework in 2024. Nucleic Acids Res 2024; 52:W521–W525 [View Article] [PubMed]
     [Google Scholar]
/content/journal/mgen/10.1099/mgen.0.001332
Loading
The dominant lineage of an emerging pathogen harbours contact-dependent inhibition systems
M Gen 11, 001332 (2025); https://doi.org/10.1099/mgen.0.001332
/content/journal/mgen/10.1099/mgen.0.001332
/content/journal/mgen/10.1099/mgen.0.001332
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Supplementary material 2

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An error occurred
Approval was partially successful, following selected items could not be processed due to error