Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics
Multi-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a vari...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/24/9692 |
| _version_ | 1797544208200892416 |
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| author | Taylor Rounds Suzana K. Straus |
| author_facet | Taylor Rounds Suzana K. Straus |
| author_sort | Taylor Rounds |
| collection | DOAJ |
| description | Multi-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a variety of ways, and lead to minimal resistance. However, the therapeutic efficacy of HDPs is limited by a number of factors, including systemic toxicity, rapid degradation, and low bioavailability. One approach to circumvent these issues is to use lipidation, i.e., the attachment of one or more fatty acid chains to the amine groups of the N-terminus or a lysine residue of an HDP. In this review, we examined lipidated analogs of 66 different HDPs reported in the literature to determine: (i) whether there is a link between acyl chain length and antibacterial activity; (ii) whether the charge and (iii) the hydrophobicity of the HDP play a role; and (iv) whether acyl chain length and toxicity are related. Overall, the analysis suggests that lipidated HDPs with improved activity over the nonlipidated counterpart had acyl chain lengths of 8–12 carbons. Moreover, active lipidated peptides attached to short HDPs tended to have longer acyl chain lengths. Neither the charge of the parent HDP nor the percent hydrophobicity of the peptide had an apparent significant impact on the antibacterial activity. Finally, the relationship between acyl chain length and toxicity was difficult to determine due to the fact that toxicity is quantified in different ways. The impact of these trends, as well as combined strategies such as the incorporation of <span style="font-variant: small-caps;">d</span>- and non-natural amino acids or alternative approaches, will be discussed in light of how lipidation may play a role in the future development of antimicrobial peptide-based alternatives to current therapeutics. |
| first_indexed | 2024-03-10T13:57:09Z |
| format | Article |
| id | doaj.art-6af6379e23f648efba65b8f0888cc72e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:57:09Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6af6379e23f648efba65b8f0888cc72e2023-11-21T01:33:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012124969210.3390/ijms21249692Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to AntibioticsTaylor Rounds0Suzana K. Straus1Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, CanadaDepartment of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, CanadaMulti-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a variety of ways, and lead to minimal resistance. However, the therapeutic efficacy of HDPs is limited by a number of factors, including systemic toxicity, rapid degradation, and low bioavailability. One approach to circumvent these issues is to use lipidation, i.e., the attachment of one or more fatty acid chains to the amine groups of the N-terminus or a lysine residue of an HDP. In this review, we examined lipidated analogs of 66 different HDPs reported in the literature to determine: (i) whether there is a link between acyl chain length and antibacterial activity; (ii) whether the charge and (iii) the hydrophobicity of the HDP play a role; and (iv) whether acyl chain length and toxicity are related. Overall, the analysis suggests that lipidated HDPs with improved activity over the nonlipidated counterpart had acyl chain lengths of 8–12 carbons. Moreover, active lipidated peptides attached to short HDPs tended to have longer acyl chain lengths. Neither the charge of the parent HDP nor the percent hydrophobicity of the peptide had an apparent significant impact on the antibacterial activity. Finally, the relationship between acyl chain length and toxicity was difficult to determine due to the fact that toxicity is quantified in different ways. The impact of these trends, as well as combined strategies such as the incorporation of <span style="font-variant: small-caps;">d</span>- and non-natural amino acids or alternative approaches, will be discussed in light of how lipidation may play a role in the future development of antimicrobial peptide-based alternatives to current therapeutics.https://www.mdpi.com/1422-0067/21/24/9692antimicrobial peptide (AMP)host-defense peptide (HDP)lipidation |
| spellingShingle | Taylor Rounds Suzana K. Straus Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics International Journal of Molecular Sciences antimicrobial peptide (AMP) host-defense peptide (HDP) lipidation |
| title | Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics |
| title_full | Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics |
| title_fullStr | Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics |
| title_full_unstemmed | Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics |
| title_short | Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics |
| title_sort | lipidation of antimicrobial peptides as a design strategy for future alternatives to antibiotics |
| topic | antimicrobial peptide (AMP) host-defense peptide (HDP) lipidation |
| url | https://www.mdpi.com/1422-0067/21/24/9692 |
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