Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i>
<i>Enterococcus faecium</i> has become an important drug-resistant nosocomial pathogen because of widespread antibiotic abuse. We developed short and chemically simple antimicrobial peptides (AMPs) with a selective amino acid composition, fixed charge, and hydrophobicity ratio based on t...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/8/1085 |
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| author | Biswajit Mishra LewisOscar Felix Anindya Basu Sai Sundeep Kollala Yashpal Singh Chhonker Narchonai Ganesan Daryl J. Murry Eleftherios Mylonakis |
| author_facet | Biswajit Mishra LewisOscar Felix Anindya Basu Sai Sundeep Kollala Yashpal Singh Chhonker Narchonai Ganesan Daryl J. Murry Eleftherios Mylonakis |
| author_sort | Biswajit Mishra |
| collection | DOAJ |
| description | <i>Enterococcus faecium</i> has become an important drug-resistant nosocomial pathogen because of widespread antibiotic abuse. We developed short and chemically simple antimicrobial peptides (AMPs) with a selective amino acid composition, fixed charge, and hydrophobicity ratio based on the core antimicrobial motif of bovine lactoferrin (LfcinB6). Among these peptides, 5L and 6L (both 12 residues long) demonstrated a narrow spectrum and high antibacterial activity against drug-resistant <i>E. faecium</i> isolates with a minimal inhibitory concentration (MIC) that ranged from 4–16 µg/mL. At 32 µg/mL, peptides 5L and 6L inhibited <i>E. faecium</i> strain C68 biofilm formation by 90% and disrupted established biofilms by 75%. At 40 µg/mL, 5L reduced 1 × 10<sup>7</sup><i>E. faecium</i> persister cells by 3 logs within 120 min of exposure, whereas 6L eliminated all persister cells within 60 min. At 0.5× MIC, 5L and 6L significantly downregulated the expression of a crucial biofilm gene <i>ace</i> by 8 folds (<i>p</i> = 0.02) and 4 folds (<i>p</i> = 0.01), respectively. At 32 µg/mL, peptides 5L and 6L both depolarized the <i>E. faecium</i> membrane, increased fluidity, and eventually ruptured the membrane. Physiologically, 5L (at 8 µg/mL) altered the tricarboxylic acid cycle, glutathione, and purine metabolism. Interestingly, in an ex vivo model of porcine skin infection, compared to no treatment, 5L (at 10× MIC) effectively eliminated all 1 × 10<sup>6</sup> exponential (<i>p</i> = 0.0045) and persister <i>E. faecium</i> cells (<i>p</i> = 0.0002). In conclusion, the study outlines a roadmap for developing narrow-spectrum selective AMPs and presents peptide 5L as a potential therapeutic candidate to be explored against <i>E. faecium</i>. |
| first_indexed | 2024-03-09T10:02:48Z |
| format | Article |
| id | doaj.art-c0ddb70f1a88495f85f16e37cc6c123c |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T10:02:48Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-c0ddb70f1a88495f85f16e37cc6c123c2023-12-01T23:19:39ZengMDPI AGAntibiotics2079-63822022-08-01118108510.3390/antibiotics11081085Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i>Biswajit Mishra0LewisOscar Felix1Anindya Basu2Sai Sundeep Kollala3Yashpal Singh Chhonker4Narchonai Ganesan5Daryl J. Murry6Eleftherios Mylonakis7Infectious Diseases Division, Warren Alpert Medical School of Brown University, Providence, RI 02903, USAInfectious Diseases Division, Warren Alpert Medical School of Brown University, Providence, RI 02903, USASchool of Pharmaceutical Sciences, Rajiv Gandhi Technological University, Bhopal 462033, IndiaDepartment of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USAInfectious Diseases Division, Warren Alpert Medical School of Brown University, Providence, RI 02903, USADepartment of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USAInfectious Diseases Division, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA<i>Enterococcus faecium</i> has become an important drug-resistant nosocomial pathogen because of widespread antibiotic abuse. We developed short and chemically simple antimicrobial peptides (AMPs) with a selective amino acid composition, fixed charge, and hydrophobicity ratio based on the core antimicrobial motif of bovine lactoferrin (LfcinB6). Among these peptides, 5L and 6L (both 12 residues long) demonstrated a narrow spectrum and high antibacterial activity against drug-resistant <i>E. faecium</i> isolates with a minimal inhibitory concentration (MIC) that ranged from 4–16 µg/mL. At 32 µg/mL, peptides 5L and 6L inhibited <i>E. faecium</i> strain C68 biofilm formation by 90% and disrupted established biofilms by 75%. At 40 µg/mL, 5L reduced 1 × 10<sup>7</sup><i>E. faecium</i> persister cells by 3 logs within 120 min of exposure, whereas 6L eliminated all persister cells within 60 min. At 0.5× MIC, 5L and 6L significantly downregulated the expression of a crucial biofilm gene <i>ace</i> by 8 folds (<i>p</i> = 0.02) and 4 folds (<i>p</i> = 0.01), respectively. At 32 µg/mL, peptides 5L and 6L both depolarized the <i>E. faecium</i> membrane, increased fluidity, and eventually ruptured the membrane. Physiologically, 5L (at 8 µg/mL) altered the tricarboxylic acid cycle, glutathione, and purine metabolism. Interestingly, in an ex vivo model of porcine skin infection, compared to no treatment, 5L (at 10× MIC) effectively eliminated all 1 × 10<sup>6</sup> exponential (<i>p</i> = 0.0045) and persister <i>E. faecium</i> cells (<i>p</i> = 0.0002). In conclusion, the study outlines a roadmap for developing narrow-spectrum selective AMPs and presents peptide 5L as a potential therapeutic candidate to be explored against <i>E. faecium</i>.https://www.mdpi.com/2079-6382/11/8/1085antimicrobial peptidesbiofilmpersisters<i>Enterococcus faecium</i> |
| spellingShingle | Biswajit Mishra LewisOscar Felix Anindya Basu Sai Sundeep Kollala Yashpal Singh Chhonker Narchonai Ganesan Daryl J. Murry Eleftherios Mylonakis Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i> Antibiotics antimicrobial peptides biofilm persisters <i>Enterococcus faecium</i> |
| title | Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i> |
| title_full | Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i> |
| title_fullStr | Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i> |
| title_full_unstemmed | Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i> |
| title_short | Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant <i>Enterococcus faecium</i> |
| title_sort | design and evaluation of short bovine lactoferrin derived antimicrobial peptides against multidrug resistant i enterococcus faecium i |
| topic | antimicrobial peptides biofilm persisters <i>Enterococcus faecium</i> |
| url | https://www.mdpi.com/2079-6382/11/8/1085 |
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