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Cited by 31Bacterial Genetics and BiotechnologyBacteriophages and microbial interactionsVibrio bacteria research studies

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The Vibrio cholerae CBASS phage defence system modulates resistance and killing by antifolate antibiotics

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Brenzinger, Susanne, Airoldi, Martina, Ogunleye, Adewale Joseph, Jugovic, Karl, Amstalden, Martin Krähenbühl, Brochado, Ana Rita·2024·Nature Microbiology
DOI 10.1038/s41564-023-01556-y

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Abstract

Toxic bacterial modules such as toxin-antitoxin systems hold antimicrobial potential, though successful applications are rare. Here we show that in Vibrio cholerae the cyclic-oligonucleotide-based anti-phage signalling system (CBASS), another example of a toxic module, increases sensitivity to antifolate antibiotics up to 10×, interferes with their synergy and ultimately enables bacterial lysis by these otherwise classic bacteriostatic antibiotics. Cyclic-oligonucleotide production by the CBASS nucleotidyltransferase DncV upon antifolate treatment confirms full CBASS activation under these conditions, and suggests that antifolates release DncV allosteric inhibition by folates. Consequently, the CBASS-antifolate interaction is specific to CBASS systems with closely related nucleotidyltransferases and similar folate-binding pockets. Last, antifolate resistance genes abolish the CBASS-antifolate interaction by bypassing the effects of on-target antifolate activity, thereby creating potential for their coevolution with CBASS. Altogether, our findings illustrate how toxic modules can impact antibiotic activity and ultimately confer bactericidal activity to classical bacteriostatic antibiotics.

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  1. Jurėnas, D., Fraikin, N., Goormaghtigh, F. & Van Melderen, L. Biology and evolution of bacterial toxin–antitoxin systems. Nat. Rev. Microbiol. 20, 335–350 (2022). · DOI
  2. Song, S. & Wood, T. K. A primary physiological role of toxin/antitoxin systems is phage inhibition. Front. Microbiol. 11, 1895 (2020). · DOI
  3. Harms, A., Brodersen, D. E., Mitarai, N. & Gerdes, K. Toxins, targets, and triggers: an overview of toxin-antitoxin biology. Mol. Cell 70, 768–784 (2018). · DOI
  4. Chan, W. T., Balsa, D. & Espinosa, M. One cannot rule them all: are bacterial toxins-antitoxins druggable? FEMS Microbiol. Rev. 39, 522–540 (2015). · DOI
  5. Lee, K.-Y. & Lee, B.-J. Structure, biology, and therapeutic application of toxin–antitoxin systems in pathogenic bacteria. Toxins 8, 305 (2016). · DOI
  6. López-Igual, R., Bernal-Bayard, J., Rodríguez-Patón, A., Ghigo, J.-M. & Mazel, D. Engineered toxin–intein antimicrobials can selectively target and kill antibiotic-resistant bacteria in mixed populations. Nat. Biotechnol. 37, 755–760 (2019). · DOI
  7. Nichols, R. J. et al. Phenotypic landscape of a bacterial cell. Cell 144, 143–156 (2011). · DOI
  8. Lopatkin, A. J. et al. Clinically relevant mutations in core metabolic genes confer antibiotic resistance. Science 371, eaba0862 (2021). · DOI
  9. Doron, S. et al. Systematic discovery of antiphage defense systems in the microbial pangenome. Science 359, eaar4120 (2018). · DOI
  10. Cohen, D. et al. Cyclic GMP–AMP signalling protects bacteria against viral infection. Nature 574, 691–695 (2019). · DOI
  11. Vassallo, C. N., Doering, C. R., Littlehale, M. L., Teodoro, G. I. C. & Laub, M. T. A functional selection reveals previously undetected anti-phage defence systems in the E. coli pangenome. Nat. Microbiol. 7, 1568–1579 (2022). · DOI
  12. Bobonis, J. et al. Bacterial retrons encode phage-defending tripartite toxin–antitoxin systems. Nature 609, 144–150 (2022). · DOI · Paper page
  13. Millman, A. et al. An expanded arsenal of immune systems that protect bacteria from phages. Cell Host Microbe 30, 1556–1569 (2022). · DOI · Paper page
  14. Burroughs, A. M., Zhang, D., Schäffer, D. E., Iyer, L. M. & Aravind, L. Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling. Nucleic Acids Res. 43, 10633–10654 (2015). · DOI
  15. Lopatina, A., Tal, N. & Sorek, R. Abortive infection: bacterial suicide as an antiviral immune strategy. Annu Rev. Virol. 7, 371–384 (2020). · DOI
  16. Makarova, K. S., Wolf, Y. I., Snir, S. & Koonin, E. V. Defense islands in bacterial and archaeal genomes and prediction of novel defense systems. J. Bacteriol. 193, 6039–6056 (2011). · DOI
  17. Gao, L. et al. Diverse enzymatic activities mediate antiviral immunity in prokaryotes. Science 369, 1077–1084 (2020). · DOI
  18. Rousset, F. et al. Phages and their satellites encode hotspots of antiviral systems. Cell Host Microbe 30, 740–753 (2022). · DOI
  19. Whiteley, A. T. et al. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature 567, 194–199 (2019). · DOI
  20. Millman, A., Melamed, S., Amitai, G. & Sorek, R. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Nat. Microbiol. 5, 1608–1615 (2020). · DOI
  21. Kranzusch, P. J. cGAS and CD-NTase enzymes: structure, mechanism, and evolution. Curr. Opin. Struct. Biol. 59, 178–187 (2019). · DOI
  22. Huiting, E. et al. Bacteriophages inhibit and evade cGAS-like immune function in bacteria. Cell 186, 864–876 (2023). · DOI
  23. Duncan-Lowey, B., McNamara-Bordewick, N. K., Tal, N., Sorek, R. & Kranzusch, P. J. Effector-mediated membrane disruption controls cell death in CBASS antiphage defense. Mol. Cell 81, 5039–5051 (2021). · DOI
  24. Ledvina, H. E. et al. An E1–E2 fusion protein primes antiviral immune signalling in bacteria. Nature https://doi.org/10.1038/s41586-022-05647-4 (2023). · DOI · Paper page
  25. Davies, B. W., Bogard, R. W., Young, T. S. & Mekalanos, J. J. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149, 358–370 (2012). · DOI
  26. Severin, G. B. et al. Direct activation of a phospholipase by cyclic GMP–AMP in El Tor Vibrio cholerae. Proc. Natl Acad. Sci. USA 115, E6048–E6055 (2018). · DOI
  27. Zhu, D. et al. Structural biochemistry of a Vibrio cholerae dinucleotide cyclase reveals cyclase activity regulation by folates. Mol. Cell 55, 931–937 (2014). · DOI
  28. Kato, K., Ishii, R., Hirano, S., Ishitani, R. & Nureki, O. Structural basis for the catalytic mechanism of DncV, bacterial homolog of cyclic GMP–AMP synthase. Structure 23, 843–850 (2015). · DOI
  29. Brochado, A. R. & Typas, A. High-throughput approaches to understanding gene function and mapping network architecture in bacteria. Curr. Opin. Microbiol. 16, 199–206 (2013). · DOI
  30. Kompis, I. M., Islam, K. & Then, R. L. DNA and RNA synthesis: antifolates. Chem. Rev. 105, 593–620 (2005). · DOI
  31. Örtengren, B., Magni, L. & Bergan, T. Development of sulphonamide–trimethoprim combinations for urinary tract infections. Infection 7, S371–S381 (1979). · DOI
  32. Eyler, R. F. & Shvets, K. Clinical pharmacology of antibiotics. CJASN 14, 1080–1090 (2019). · DOI
  33. Kwon, Y. K. et al. A domino effect in antifolate drug action in Escherichia coli. Nat. Chem. Biol. 4, 602–608 (2008). · DOI
  34. Bushby, S. R. M. Trimethoprim–sulfamethoxazole: in vitro microbiological aspects. J. Infect. Dis. 128, S442–S462 (1973). · DOI
  35. Phillips, I. & Warren, C. Activity of sulfamethoxazole and trimethoprim against Bacteroides fragilis. Antimicrob. Agents Chemother. 9, 736–740 (1976). · DOI
  36. Chevereau, G. & Bollenbach, T. Systematic discovery of drug interaction mechanisms. Mol. Syst. Biol. 11, 807 (2015). · DOI
  37. Loewe, S. Die quantitativen Probleme der Pharmakologie. Ergeb. Physiol. 27, 47–187 (1928). · DOI
  38. Hall, M. J., Middleton, R. F. & Westmacott, D. The fractional inhibitory concentration (FIC) index as a measure of synergy. J. Antimicrob. Chemother. 11, 427–433 (1983). · DOI
  39. Woods, D. D. The relation of p-aminobenzoic acid to the mechanism of the action of sulphanilamide. Br. J. Exp. Pathol. 21, 74–90 (1940).
  40. Estrada, A., Wright, D. L. & Anderson, A. C. Antibacterial antifolates: from development through resistance to the next generation. Cold Spring Harb. Perspect. Med 6, a028324 (2016). · DOI
  41. Waldor, M. K., Tschäpe, H. & Mekalanos, J. J. A new type of conjugative transposon encodes resistance to sulfamethoxazole, trimethoprim, and streptomycin in Vibrio cholerae O139. J. Bacteriol. 178, 4157–4165 (1996). · DOI
  42. Lau, R. K., Enustun, E., Gu, Y., Nguyen, J. V. & Corbett, K. D. A conserved signaling pathway activates bacterial CBASS immune signaling in response to DNA damage. EMBO J. 41, e111540 (2022). · DOI
  43. Jenson, J. M., Li, T., Du, F., Ea, C.-K. & Chen, Z. J. Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence. Nature 616, 326–331 (2023). · DOI
  44. Minato, Y. et al. Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole. Nat. Commun. 9, 1003 (2018). · DOI
  45. Siegele, D. A. & Hu, J. C. Gene expression from plasmids containing the araBAD promoter at subsaturating inducer concentrations represents mixed populations. Proc. Natl Acad. Sci. USA 94, 8168–8172 (1997). · DOI
  46. Maier, L. et al. Unravelling the collateral damage of antibiotics on gut bacteria. Nature 599, 120–124 (2021). · DOI
  47. Severin, G. B. et al. Activation of a Vibrio cholerae CBASS anti-phage system by quorum sensing and folate depletion. mBio https://doi.org/10.1128/mbio.00875-23 (2023). · DOI
  48. Cash, R. A., Northrup, R. S. & Mizanur Rahman, A. S. M. Trimethoprim and sulfamethoxazole in clinical cholera: comparison with tetracycline. J. Infect. Dis. 128, S749–S753 (1973). · DOI
  49. Hughes, S. R., Kay, P. & Brown, L. E. Global synthesis and critical evaluation of pharmaceutical data sets collected from river systems. Environ. Sci. Technol. 47, 661–677 (2013). · DOI
  50. Omuferen, L. O., Maseko, B. & Olowoyo, J. O. Occurrence of antibiotics in wastewater from hospital and convectional wastewater treatment plants and their impact on the effluent receiving rivers: current knowledge between 2010 and 2019. Environ. Monit. Assess. 194, 306 (2022). · DOI
  51. Khlebnikov, A., Datsenko, K. A., Skaug, T., Wanner, B. L. & Keasling, J. D. Homogeneous expression of the PBAD promoter in Escherichia coli by constitutive expression of the low-affinity high-capacity AraE transporter. Microbiology 147, 3241–3247 (2001). · DOI
  52. Stutzmann, S. & Blokesch, M. Comparison of chitin‐induced natural transformation in pandemic Vibrio cholerae O1 El Tor strains. Environ. Microbiol. 22, 4149–4166 (2020). · DOI
  53. Lassak, J., Henche, A.-L., Binnenkade, L. & Thormann, K. M. ArcS, the cognate sensor kinase in an atypical arc system of Shewanella oneidensis MR-1. Appl. Environ. Microbiol. 76, 3263–3274 (2010). · DOI
  54. Brenzinger, S. et al. Structural and proteomic changes in viable but non-culturable Vibrio cholerae. Front. Microbiol. 10, 793 (2019). · DOI
  55. Gibson, D. G. et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat. Methods 6, 343–345 (2009). · DOI
  56. Guzman, L. M., Belin, D., Carson, M. J. & Beckwith, J. Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD promoter. J. Bacteriol. 177, 4121–4130 (1995). · DOI
  57. Sinai, R., Hammerberg, S., Marks, M. I. & Pai, C. H. In vitro susceptibility of Haemophilus influenzae to sulfamethoxazole–trimethoprim and cefaclor, cephalexin, and cephradine. Antimicrob. Agents Chemother. 13, 861–864 (1978). · DOI
  58. Ritz, C., Baty, F., Streibig, J. C. & Gerhard, D. Dose-response analysis using R. PLoS ONE 10, e0146021 (2015). · DOI
  59. Wang, C.-Y. et al. Metabolome and proteome analyses reveal transcriptional misregulation in glycolysis of engineered E. coli. Nat. Commun. 12, 4929 (2021).
  60. Chen, I.-M. A. et al. The IMG/M data management and analysis system v.7: content updates and new features. Nucleic Acids Res. 51, D723–D732 (2023). · DOI
  61. Chen, I.-M. A. et al. The IMG/M data management and analysis system v.6.0: new tools and advanced capabilities. Nucleic Acids Res. 49, D751–D763 (2020). · DOI
  62. Price, M. N., Dehal, P. S. & Arkin, A. P. FastTree 2—approximately maximum-likelihood trees for large alignments. PLoS ONE 5, e9490 (2010). · DOI · Paper page
  63. Paradis, E. & Schliep, K. ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R. Bioinformatics 35, 526–528 (2019). · DOI
  64. Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022). · DOI · Paper page
  65. Morris, G. M. et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785–2791 (2009). · DOI
  66. Edgar, R. C. Muscle5: high-accuracy alignment ensembles enable unbiased assessments of sequence homology and phylogeny. Nat. Commun. 13, 6968 (2022). · DOI

Metadata

Authors
Brenzinger, S., Airoldi, M., Ogunleye, A. J., Jugovic, K., Amstalden, M. K., & Brochado, A. R.
Affiliations
University of Würzburg (DE)
Corresponding author
Brochado, Ana Rita
ORCID
Venue
Nature Microbiology
Publisher
Springer Science and Business Media LLC
Published
2024-01-03
Volume
9
Issue
1
Pages
251-262
ISSN
2058-5276 (ISSN-L)
DOI
10.1038/s41564-023-01556-y
OpenAlex
W4390571582
Cited by
31
References
4
Citations by year
2026: 12 · 2025: 12 · 2024: 4
FWCI
7.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Microbiology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Hector Fellow Academy (HRCDA2020 to ARB)
  • Deutsche Forschungsgemeinschaft (390838134, GO 3161/1-1)
  • Julius Maximilians University of Würzburg, GSLS Postdoc plus program
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
  • Life Sciences › Immunology and Microbiology › Microbiology › Vibrio bacteria research studies
Keywords
Vibrio cholerae, C-BASS, toxin-antitoxin systems, sulfonamides, folate binding, allosteric inhibition, antibiotic synergy, bactericidal activity, bacterial lysis, antibiotic resistance genes, coevolution
MeSH terms
Anti-Bacterial Agents, Bacteria, Bacteriophages, Folic Acid Antagonists, Oligonucleotides, Vibrio cholerae

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