Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup>
<i>Streptomyces lunaelactis</i> strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a <i>Strep...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1114 |
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| author | Loïc Martinet Aymeric Naômé Lucas C. D. Rezende Déborah Tellatin Bernard Pignon Jean-Denis Docquier Filomena Sannio Dominique Baiwir Gabriel Mazzucchelli Michel Frédérich Sébastien Rigali |
| author_facet | Loïc Martinet Aymeric Naômé Lucas C. D. Rezende Déborah Tellatin Bernard Pignon Jean-Denis Docquier Filomena Sannio Dominique Baiwir Gabriel Mazzucchelli Michel Frédérich Sébastien Rigali |
| author_sort | Loïc Martinet |
| collection | DOAJ |
| description | <i>Streptomyces lunaelactis</i> strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a <i>Streptomyces</i> species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of <i>S</i>. <i>lunaelactis</i> strains for which in silico analysis predicted the production of nonribosomal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts of <i>S</i>. <i>lunaelactis</i> strains either holding or not holding BGC 28a combined with MS/MS-guided peptidogenomics and <sup>1</sup>H/<sup>13</sup>C NMR allowed us to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, with 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a significant bactericidal activity of lunaemycins against Gram-positive bacteria, including multi-drug resistant clinical isolates. Our work demonstrates how an accurate in silico analysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites. |
| first_indexed | 2024-03-09T12:25:44Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:25:44Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-605a9f4e7c5a4d1abfa18a28eb60599a2023-11-30T22:35:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242111410.3390/ijms24021114Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup>Loïc Martinet0Aymeric Naômé1Lucas C. D. Rezende2Déborah Tellatin3Bernard Pignon4Jean-Denis Docquier5Filomena Sannio6Dominique Baiwir7Gabriel Mazzucchelli8Michel Frédérich9Sébastien Rigali10InBioS—Centre for Protein Engineering, Institut de Chimie B6a, University of Liège, B-4000 Liege, BelgiumInBioS—Centre for Protein Engineering, Institut de Chimie B6a, University of Liège, B-4000 Liege, BelgiumHedera-22, Boulevard du Rectorat 27b, B-4000 Liege, BelgiumInBioS—Centre for Protein Engineering, Institut de Chimie B6a, University of Liège, B-4000 Liege, BelgiumInBioS—Centre for Protein Engineering, Institut de Chimie B6a, University of Liège, B-4000 Liege, BelgiumInBioS—Centre for Protein Engineering, Institut de Chimie B6a, University of Liège, B-4000 Liege, BelgiumDipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, 53100 Siena, ItalyGIGA Proteomics Facility, University of Liege, B-4000 Liege, BelgiumMass Spectrometry Laboratory, MolSys Research Unit, University of Liege, B-4000 Liege, BelgiumLaboratory of Pharmacognosy, Center of Interdisciplinary Research on Medicines (CIRM), University of Liege, B-4000 Liege, BelgiumInBioS—Centre for Protein Engineering, Institut de Chimie B6a, University of Liège, B-4000 Liege, Belgium<i>Streptomyces lunaelactis</i> strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a <i>Streptomyces</i> species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of <i>S</i>. <i>lunaelactis</i> strains for which in silico analysis predicted the production of nonribosomal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts of <i>S</i>. <i>lunaelactis</i> strains either holding or not holding BGC 28a combined with MS/MS-guided peptidogenomics and <sup>1</sup>H/<sup>13</sup>C NMR allowed us to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, with 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a significant bactericidal activity of lunaemycins against Gram-positive bacteria, including multi-drug resistant clinical isolates. Our work demonstrates how an accurate in silico analysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites.https://www.mdpi.com/1422-0067/24/2/1114antibioticscryptic metabolitesnatural compoundsAnti-MRSAmoonmilkcave microbiology |
| spellingShingle | Loïc Martinet Aymeric Naômé Lucas C. D. Rezende Déborah Tellatin Bernard Pignon Jean-Denis Docquier Filomena Sannio Dominique Baiwir Gabriel Mazzucchelli Michel Frédérich Sébastien Rigali Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup> International Journal of Molecular Sciences antibiotics cryptic metabolites natural compounds Anti-MRSA moonmilk cave microbiology |
| title | Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup> |
| title_full | Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup> |
| title_fullStr | Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup> |
| title_full_unstemmed | Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup> |
| title_short | Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller <i>Streptomyces lunaelactis</i> MM109<sup>T</sup> |
| title_sort | lunaemycins new cyclic hexapeptide antibiotics from the cave moonmilk dweller i streptomyces lunaelactis i mm109 sup t sup |
| topic | antibiotics cryptic metabolites natural compounds Anti-MRSA moonmilk cave microbiology |
| url | https://www.mdpi.com/1422-0067/24/2/1114 |
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