Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis
Tuberculosis is a highly prevalent infectious disease with more than 1.5 million fatalities each year. Antibiotic treatment is available, but intolerable side effects and an increasing rate of drug-resistant strains of Mycobacterium tuberculosis (Mtb) may hamper successful outcomes. Antimicrobial pe...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2020.618278/full |
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| author | Reiner Noschka Fabian Gerbl Florian Löffler Jan Kubis Armando A. Rodríguez Armando A. Rodríguez Daniel Mayer Mark Grieshober Armin Holch Martina Raasholm Wolf-Georg Forssmann Barbara Spellerberg Sebastian Wiese Gilbert Weidinger Ludger Ständker Steffen Stenger |
| author_facet | Reiner Noschka Fabian Gerbl Florian Löffler Jan Kubis Armando A. Rodríguez Armando A. Rodríguez Daniel Mayer Mark Grieshober Armin Holch Martina Raasholm Wolf-Georg Forssmann Barbara Spellerberg Sebastian Wiese Gilbert Weidinger Ludger Ständker Steffen Stenger |
| author_sort | Reiner Noschka |
| collection | DOAJ |
| description | Tuberculosis is a highly prevalent infectious disease with more than 1.5 million fatalities each year. Antibiotic treatment is available, but intolerable side effects and an increasing rate of drug-resistant strains of Mycobacterium tuberculosis (Mtb) may hamper successful outcomes. Antimicrobial peptides (AMPs) offer an alternative strategy for treatment of infectious diseases in which conventional antibiotic treatment fails. Human serum is a rich resource for endogenous AMPs. Therefore, we screened a library generated from hemofiltrate for activity against Mtb. Taking this unbiased approach, we identified Angiogenin as the single compound in an active fraction. The antimicrobial activity of endogenous Angiogenin against extracellular Mtb could be reproduced by synthetic Angiogenin. Using computational analysis, we identified the hypothetical active site and optimized the lytic activity by amino acid exchanges. The resulting peptide-Angie1-limited the growth of extra‐ and intracellular Mtb and the fast-growing pathogens Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Toward our long-term goal of evaluating Angie1 for therapeutic efficacy in vivo, we demonstrate that the peptide can be efficiently delivered into human macrophages via liposomes and is not toxic for zebrafish embryos. Taken together, we define Angiogenin as a novel endogenous AMP and derive the small, bioactive fragment Angie1, which is ready to be tested for therapeutic activity in animal models of tuberculosis and infections with fast-growing bacterial pathogens. |
| first_indexed | 2024-12-21T11:09:21Z |
| format | Article |
| id | doaj.art-4c71e6dd4c7540e7a3b18b1486d5c991 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-21T11:09:21Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-4c71e6dd4c7540e7a3b18b1486d5c9912022-12-21T19:06:08ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-01-011110.3389/fmicb.2020.618278618278Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosisReiner Noschka0Fabian Gerbl1Florian Löffler2Jan Kubis3Armando A. Rodríguez4Armando A. Rodríguez5Daniel Mayer6Mark Grieshober7Armin Holch8Martina Raasholm9Wolf-Georg Forssmann10Barbara Spellerberg11Sebastian Wiese12Gilbert Weidinger13Ludger Ständker14Steffen Stenger15Institute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyCore Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, GermanyCore Facility of Functional Peptidomics, Ulm University, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyInstitute of Biochemistry and Molecular Biology, Ulm University, Ulm, GermanyPharis Biotec GmbH, Hannover, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyCore Unit Mass Spectrometry and Proteomics, Ulm University, Ulm, GermanyInstitute of Biochemistry and Molecular Biology, Ulm University, Ulm, GermanyCore Facility of Functional Peptidomics, Ulm University, Ulm, GermanyInstitute of Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, GermanyTuberculosis is a highly prevalent infectious disease with more than 1.5 million fatalities each year. Antibiotic treatment is available, but intolerable side effects and an increasing rate of drug-resistant strains of Mycobacterium tuberculosis (Mtb) may hamper successful outcomes. Antimicrobial peptides (AMPs) offer an alternative strategy for treatment of infectious diseases in which conventional antibiotic treatment fails. Human serum is a rich resource for endogenous AMPs. Therefore, we screened a library generated from hemofiltrate for activity against Mtb. Taking this unbiased approach, we identified Angiogenin as the single compound in an active fraction. The antimicrobial activity of endogenous Angiogenin against extracellular Mtb could be reproduced by synthetic Angiogenin. Using computational analysis, we identified the hypothetical active site and optimized the lytic activity by amino acid exchanges. The resulting peptide-Angie1-limited the growth of extra‐ and intracellular Mtb and the fast-growing pathogens Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Toward our long-term goal of evaluating Angie1 for therapeutic efficacy in vivo, we demonstrate that the peptide can be efficiently delivered into human macrophages via liposomes and is not toxic for zebrafish embryos. Taken together, we define Angiogenin as a novel endogenous AMP and derive the small, bioactive fragment Angie1, which is ready to be tested for therapeutic activity in animal models of tuberculosis and infections with fast-growing bacterial pathogens.https://www.frontiersin.org/articles/10.3389/fmicb.2020.618278/fullantimicrobial peptideMycobacterium tuberculosisendogenous proteinantibacterialhuman |
| spellingShingle | Reiner Noschka Fabian Gerbl Florian Löffler Jan Kubis Armando A. Rodríguez Armando A. Rodríguez Daniel Mayer Mark Grieshober Armin Holch Martina Raasholm Wolf-Georg Forssmann Barbara Spellerberg Sebastian Wiese Gilbert Weidinger Ludger Ständker Steffen Stenger Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis Frontiers in Microbiology antimicrobial peptide Mycobacterium tuberculosis endogenous protein antibacterial human |
| title | Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis |
| title_full | Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis |
| title_fullStr | Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis |
| title_full_unstemmed | Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis |
| title_short | Unbiased Identification of Angiogenin as an Endogenous Antimicrobial Protein With Activity Against Virulent Mycobacterium tuberculosis |
| title_sort | unbiased identification of angiogenin as an endogenous antimicrobial protein with activity against virulent mycobacterium tuberculosis |
| topic | antimicrobial peptide Mycobacterium tuberculosis endogenous protein antibacterial human |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2020.618278/full |
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