CoChat
Sign Up
PreprintCited by 4Bacterial Genetics and BiotechnologyAntibiotic Resistance in BacteriaBiochemical and Structural Characterization

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Unraveling the prevalence and multifaceted roles of accessory peptide deformylases in bacterial adaptation and resistance

Open access
Lambérioux, Morgan, Ducos-Galand, Magaly, Kaminski, Pierre-Alexandre, Littner, Eloi, Betton, Jean-Michel, Mechaly, Ariel, Haouz, Ahmed, Mazel, Didier·2025·Molecular Biology and Evolution
DOI 10.1101/2025.06.06.657839PMC PMC12690207

Preprint — published as 10.1093/molbev/msaf311

Open this paper in CoChat — free accountOpen PDF

Abstract

Peptide deformylases (PDFs) are enzymes that are essential for bacterial viability and attractive targets for antibiotic development. Yet, despite their conserved function, many bacteria encode multiple PDFs, a genomic feature whose prevalence and implications remain largely unexplored. Here, we reveal that nearly half of all bacterial genomes carry more than one PDF gene, frequently embedded within mobile genetic elements such as plasmids and integrons. In Vibrio cholerae , the accessory PDF (Def2 VCH ) confers reduced susceptibility to actinonin (ACT), the most studied PDF inhibitor, while still supporting bacterial growth in absence of the canonical PDF copies (Def1 VCH ). Crystallographic analysis shows that this reduced susceptibility stems from an arginine-to-tyrosine substitution that probably reduces ACT binding. Strikingly, this resistance signature is shared by integron-encoded PDFs, and transfer of an integron-encoded PDF cassette from Pseudoxanthomonas into a susceptible V. cholerae is sufficient to abolish ACT susceptibility. These findings expose a cryptic reservoir of resistance within the bacterial mobilome and highlight a challenge to the therapeutic potential of PDF-targeting antibiotics: resistance may not only emerge, but is already encoded, mobile, and ready to spread.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2025.06.06.657839

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 86

  1. 10.1038/S41586-024-07487-W · DOI · Paper page
  2. 2021, Structural insights into the interplay of protein biogenesis factors with the 70S ribosome, Struct Lond Engl, 1993, 755
  3. 10.1016/S0924-8579(03)00114-6 · DOI
  4. Ares-Arroyo, M. , Nucci, A. , and Rocha, E.P.C. (2024) Identification of novel origins of transfer across bacterial plasmids. 2024.01.30.577996 https://www.biorxiv.org/content/10.1101/2024.01.30.577996v1. Accessed June 12, 2024. · DOI
  5. 10.1016/j.jmb.2019.02.002 · DOI
  6. 10.1002/pmic.201500027 · DOI
  7. 10.1038/nature06683 · DOI
  8. 10.1038/s41598-021-03969-3 · DOI
  9. 10.1111/j.1365-2958.2007.05867.x · DOI
  10. 10.1186/1471-2164-11-588 · DOI
  11. Bricogne, G. , Blanc, E. , Brandl, M. , Flensburg, C. , Keller, P. , Paciorek, W ., et al. (2017) BUSTER version 2.11.1. Cambridge, United Kingdom : Global Phasing Ltd .
  12. 10.1093/nar/gks508 · DOI · Paper page
  13. 10.1021/acssynbio.6b00081 · DOI
  14. 10.1021/bi9711543 · DOI
  15. 10.1021/bi992245y · DOI
  16. Chen, J. , Pfeifer, K. , Steensen, K. , Crooke, A.M. , Wolfram, M. , Bobonis, J. , Lopatina, A. , Bartlau, N. , Hussain, F.A. , Balskus, E.P. , Polz, M.F. and Blainey, P.C. (2025). Bacterial peptide deformylase inhibitors induce prophages in competitors. bioRxiv. · DOI
  17. 10.1038/nbt.1582 · DOI
  18. 10.1128/AAC.45.2.563-570.2001 · DOI
  19. 10.1126/science.1219385 · DOI
  20. Costa, J.H. , Adams, E.E. , and Johnston, C.W. (2024) Discovery and description of gammanonin: a widely distributed natural product from Gammaproteobacteria. 2024.08.13.607837 https://www.biorxiv.org/content/10.1101/2024.08.13.607837v1. Accessed February 14, 2025. · DOI
  21. 10.1038/s41586-020-1990-9 · DOI
  22. 10.1093/nar/gkw319 · DOI
  23. 10.1073/pnas.1406478111 · DOI
  24. 10.1126/science.ads0768 · DOI
  25. 10.1128/AAC.01103-06 · DOI
  26. 2018, Vibrio cholerae chromosome 2 copy number is controlled by the methylation-independent binding of its monomeric initiator to the chromosome 1 crtS site, Nucleic Acids Res, 46, 10145
  27. 2017, The signal recognition particle contacts uL23 and scans substrate translation inside the ribosomal tunnel, Nat Microbiol, 2, 1
  28. 2017, The Divided Bacterial Genome: Structure, Function, and Evolution. Microbiol Mol Biol Rev MMBR, 81, e00019
  29. 10.1128/AAC.01340-08 · DOI
  30. 10.1107/S0907444904019158 · DOI · Paper page
  31. 10.1128/microbiolspec.mdna3-0019–2014 · DOI
  32. Ford, J.J. , Santos-Aberturas, J. , Hems, E.S. , Sallmen, J.W. , Bögeholz, L.A.K. , Polturak, G. , et al. (2024) Discovery of lydiamycin A biosynthetic gene cluster in the plant pathogen Rhodococcus fascians guides structural revision and identification of molecular target. 2024.11.13.623425 https://www.biorxiv.org/content/10.1101/2024.11.13.623425v1. Accessed November 19, 2024. · DOI
  33. 10.1093/nar/gkab903 · DOI
  34. 10.1128/AAC.49.4.1468-1476.2005 · DOI
  35. 10.7554/eLife.96317.3 · DOI
  36. 10.1038/nmeth.1318 · DOI
  37. 2004, Protein N-terminal methionine excision, Cell Mol Life Sci CMLS, 61, 1455
  38. 10.1016/j.tibs.2009.04.003 · DOI
  39. 10.1016/j.biochi.2014.11.008 · DOI
  40. 1975, Studies concerning the antibiotic actinonin, Part I. The constitution of actinonin. A natural hydroxamic acid with antibiotic activity. J Chem Soc Perkin, 1, 819
  41. 1962, Actinonin: an Antibiotic Substance produced by an Actinomycete, Nature, 195, 701, 10.1038/195701b0 · DOI
  42. 10.1038/s41598-017-11329-3 · DOI
  43. 10.1093/nar/gku194 · DOI
  44. 10.1128/jb.174.13.4294-4301.1992 · DOI
  45. 10.1016/S0022-2836(02)00549-1 · DOI
  46. 10.1099/00221287-147-7-1783 · DOI
  47. 10.1016/j.tim.2009.12.010 · DOI
  48. 10.1093/molbev/msx281 · DOI · Paper page
  49. 10.2174/0929867054367194 · DOI
  50. 10.1126/science.ads0915 · DOI · Paper page
  51. 10.3390/pathogens10020165 · DOI
  52. 10.1107/S2059798319011471 · DOI · Paper page
  53. 10.1038/s41564-023-01548-y · DOI
  54. 10.1128/mbio.02296-16 · DOI
  55. 10.1038/s41467-021-23167-z · DOI
  56. 10.1128/AAC.45.9.2432-2435.2001 · DOI
  57. 10.1128/AAC.44.7.1825-1831.2000 · DOI
  58. 10.1006/jmbi.1996.0835 · DOI
  59. 10.1038/341245a0 · DOI
  60. 10.1002/j.1460-2075.1994.tb06335.x · DOI
  61. 10.1107/S0021889807021206 · DOI · Paper page
  62. 10.1038/nrmicro2670 · DOI · Paper page
  63. 10.1186/1471-2180-6-39 · DOI
  64. 10.1126/science.1120096 · DOI
  65. 10.1128/jb.175.23.7737-7740.1993 · DOI
  66. 10.1093/molbev/msaa015 · DOI · Paper page
  67. 10.1038/S41592-022-01488-1 · DOI · Paper page
  68. 10.1016/S0021-9258(19)50166-1 · DOI
  69. Néron, B. , Denise, R. , Coluzzi, C. , Touchon, M. , Rocha, E.P.C. , and Abby, S.S. (2023) MacSyFinder v2: Improved modelling and search engine to identify molecular systems in genomes. Peer Community J 3 https://peercommunityjournal.org/articles/10.24072/pcjournal.250/. Accessed July 16, 2024. · DOI
  70. 10.3390/microorganisms10040700 · DOI
  71. 10.1073/pnas.0602171103 · DOI
  72. 10.1128/mbio.01851-22 · DOI
  73. 10.1038/s41467-024-45757-3 · DOI
  74. Rabe, B.A. , and Cepko, C. (2020) A Simple Enhancement for Gibson Isothermal Assembly. 2020.06.14.150979 https://www.biorxiv.org/content/10.1101/2020.06.14.150979v1. Accessed June 7, 2024. · DOI
  75. Rill, A. , Westphalen, M. , Lamberioux, M. , Huber, E. , Chekaiban, J. , Mazel, D. , Groll, M. and Bode, H.B. (2025). Identification and biosynthesis of xildivaline, a novel and widespread peptide deformylase inhibitor from Gammaproteobacteria. bioRxiv. · DOI
  76. 10.1038/clpt.2011.101 · DOI
  77. 10.1016/j.tig.2008.01.002 · DOI
  78. 10.1038/nsmb.2615 · DOI
  79. 2015, Peptide deformylase: a new target in antibacterial, antimalarial and anticancer drug discovery, Curr Med Chem, 22, 214
  80. 10.1007/978-1-4939-9877-7_14 · DOI
  81. 10.1093/nar/gkab412 · DOI
  82. 10.1107/S0907444911007773 · DOI
  83. 2019, High-Throughput Crystallization Pipeline at the Crystallography Core Facility of the Institut Pasteur, Mol Basel Switz, 24, 4451
  84. 10.1016/j.jmb.2022.167535 · DOI
  85. Yang, N. , and Sun, C. (2016) The Inhibition and Resistance Mechanisms of Actinonin, Isolated from Marine Streptomyces sp. NHF165, against Vibrio anguillarum. Front Microbiol 7 https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.01467/full. Accessed April 10, 2024. · DOI
  86. 10.1038/s41467-019-14240-9 · DOI

Metadata

Authors
Lambérioux, M., Ducos-Galand, M., Kaminski, P.-A., Littner, E., Betton, J.-M., Mechaly, A., Haouz, A., & Mazel, D.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Institut Pasteur, Université Paris Cité, Unité Plasticité du Génome Bactérien, CNRS UMR3525, Paris, France
  • Institut Pasteur (FR)
  • Institut Pasteur, Crystallography Platform-C2RT, CNRS-UMR 3528, Université Paris Cité, Paris, France
Corresponding author
Mazel, Didier
ORCID
Venue
Molecular Biology and Evolution
Publisher
openRxiv
Published
2025-06-06
Volume
42
Issue
12
ISSN
0737-4038 (ISSN-L)
DOI
10.1101/2025.06.06.657839
PMC
PMC12690207
OpenAlex
W4416813535
Cited by
4
References
1
Citations by year
2026: 1 · 2025: 3
FWCI
2.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Biology and Evolution (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
Funders
  • Pfizer
  • Fondation pour la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Institut Pasteur de Tunis
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
Keywords
peptide deformylase, Vibrio cholerae, mobile genetic elements, Pseudoxanthomonas, bacterial adaptation
MeSH terms
Amidohydrolases, Bacterial Proteins, Vibrio cholerae, Drug Resistance, Bacterial, Integrons

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review