A Potent Host Defense Peptide Triggers DNA Damage and Is Active against Multidrug-Resistant Gram-Negative Pathogens
kan) and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to show in cellulae that DNA damage occurs upon treatment with Clavanin A. In vitro assays demonstrated that Zn(II) ions are required for the nuclease activity of the peptide. The quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the mechanism of DNA damage. In the rate-determining step of the proposed mechanism, due to its Lewis acidity, the Zn(II) ion activates the scissile P-O bond of DNA and creates a hydroxyl nucleophile from a water molecule. A subsequent attack by this group to the electrophilic phosphorus cleaves the scissile phosphoester bond. Additionally, we utilized bacterial cytological profiling (BCP), circular dichroism (CD) spectroscopy in the presence of lipid vesicles, and surface plasmon resonance combined with electrical impedance spectroscopy in order to address the apparent discrepancies between our results and the previous studies regarding the mechanism of action of Clavanin A. Finally, our approach may lead to the identification of additional Clavanin A like HDPs and promote the development of antimicrobial peptide based therapeutics.
| Errataetall: |
ErratumIn: ACS Infect Dis. 2020 Sep 11;6(9):2542. - PMID 32813488 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
ACS infectious diseases - 6(2020), 5 vom: 08. Mai, Seite 1250-1263 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Juliano, Samuel A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.06.2021 Date Revised 16.06.2021 published: Print-Electronic ErratumIn: ACS Infect Dis. 2020 Sep 11;6(9):2542. - PMID 32813488 Citation Status MEDLINE |
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| doi: |
10.1021/acsinfecdis.0c00051 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308369270 |
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| 041 | |a eng | ||
| 100 | 1 | |a Juliano, Samuel A |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Potent Host Defense Peptide Triggers DNA Damage and Is Active against Multidrug-Resistant Gram-Negative Pathogens |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 16.06.2021 | ||
| 500 | |a Date Revised 16.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: ACS Infect Dis. 2020 Sep 11;6(9):2542. - PMID 32813488 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Gram-negative bacteria are some of the biggest threats to public health due to a large prevalence of antibiotic resistance. The difficulty in treating bacterial infections, stemming from their double membrane structure combined with efflux pumps in the outer membrane, has resulted in a much greater need for antimicrobials with activity against these pathogens. Tunicate host defense peptide (HDP), Clavanin A, is capable of not only inhibiting Gram-negative growth but also potentiating activity in the presence of Zn(II). Here, we provide evidence that the improvements of Clavanin A activity in the presence of Zn(II) are due to its novel mechanism of action. We employed E. coli TD172 (ΔrecA::kan) and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to show in cellulae that DNA damage occurs upon treatment with Clavanin A. In vitro assays demonstrated that Zn(II) ions are required for the nuclease activity of the peptide. The quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the mechanism of DNA damage. In the rate-determining step of the proposed mechanism, due to its Lewis acidity, the Zn(II) ion activates the scissile P-O bond of DNA and creates a hydroxyl nucleophile from a water molecule. A subsequent attack by this group to the electrophilic phosphorus cleaves the scissile phosphoester bond. Additionally, we utilized bacterial cytological profiling (BCP), circular dichroism (CD) spectroscopy in the presence of lipid vesicles, and surface plasmon resonance combined with electrical impedance spectroscopy in order to address the apparent discrepancies between our results and the previous studies regarding the mechanism of action of Clavanin A. Finally, our approach may lead to the identification of additional Clavanin A like HDPs and promote the development of antimicrobial peptide based therapeutics | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a Gram-negative pathogens | |
| 650 | 4 | |a host defense peptide | |
| 650 | 4 | |a multidrug resistance | |
| 650 | 7 | |a Antimicrobial Cationic Peptides |2 NLM | |
| 650 | 7 | |a Blood Proteins |2 NLM | |
| 650 | 7 | |a clavanin A |2 NLM | |
| 700 | 1 | |a Serafim, Leonardo F |e verfasserin |4 aut | |
| 700 | 1 | |a Duay, Searle S |e verfasserin |4 aut | |
| 700 | 1 | |a Heredia Chavez, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Gaurav |e verfasserin |4 aut | |
| 700 | 1 | |a Rooney, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Comert, Fatih |e verfasserin |4 aut | |
| 700 | 1 | |a Pierce, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Radulescu, Andrei |e verfasserin |4 aut | |
| 700 | 1 | |a Cotten, Myriam L |e verfasserin |4 aut | |
| 700 | 1 | |a Mihailescu, Mihaela |e verfasserin |4 aut | |
| 700 | 1 | |a May, Eric R |e verfasserin |4 aut | |
| 700 | 1 | |a Greenwood, Alexander I |e verfasserin |4 aut | |
| 700 | 1 | |a Prabhakar, Rajeev |e verfasserin |4 aut | |
| 700 | 1 | |a Angeles-Boza, Alfredo M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ACS infectious diseases |d 2015 |g 6(2020), 5 vom: 08. Mai, Seite 1250-1263 |w (DE-627)NLM248280775 |x 2373-8227 |7 nnns |
| 773 | 1 | 8 | |g volume:6 |g year:2020 |g number:5 |g day:08 |g month:05 |g pages:1250-1263 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acsinfecdis.0c00051 |3 Volltext |
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