Maria Rosa Loffredo, Bruno Casciaro, Rosa Bellavita, Cassandra Troiano, Diego Brancaccio, Floriana Cappiello, Francesco Merlino, Stefania Galdiero, Giancarlo Fabrizi, Paolo Grieco, Lorenzo Stella, Alfonso Carotenuto, Maria Luisa Mangoni
{"title":"抗菌肽 Esc(1-21) 的策略性单残基置换赋予其对抗金黄色葡萄球菌的活性,包括耐药性和生物膜表型。","authors":"Maria Rosa Loffredo, Bruno Casciaro, Rosa Bellavita, Cassandra Troiano, Diego Brancaccio, Floriana Cappiello, Francesco Merlino, Stefania Galdiero, Giancarlo Fabrizi, Paolo Grieco, Lorenzo Stella, Alfonso Carotenuto, Maria Luisa Mangoni","doi":"10.1021/acsinfecdis.4c00130","DOIUrl":null,"url":null,"abstract":"<p><p><i>Staphylococcus aureus</i>, a bacterium resistant to multiple drugs, is a significant cause of illness and death worldwide. Antimicrobial peptides (AMPs) provide an excellent potential strategy to cope with this threat. Recently, we characterized a derivative of the frog-skin AMP esculentin-1a, Esc(1-21) (<b>1</b>) that is endowed with potent activity against Gram-negative bacteria but poor efficacy against Gram-positive strains. In this study, three analogues of peptide <b>1</b> were designed by replacing Gly<sup>8</sup> with α-aminoisobutyric acid (Aib), Pro, and dPro (<b>2</b>-<b>4</b>, respectively). The single substitution Gly<sup>8</sup> → Aib<sup>8</sup> in peptide <b>2</b> makes it active against the planktonic form of Gram-positive bacterial strains, especially <i>Staphylococcus aureus</i>, including multidrug-resistant clinical isolates, with an improved biostability without resulting in cytotoxicity to mammalian cells. Moreover, peptide <b>2</b> showed a higher antibiofilm activity than peptide <b>1</b> against both reference and clinical isolates of <i>S</i>. <i>aureus</i>. Peptide <b>2</b> was also able to induce rapid bacterial killing, suggesting a membrane-perturbing mechanism of action. Structural analysis of the most active peptide <b>2</b> evidenced that the improved biological activity of peptide <b>2</b> is the consequence of a combination of higher biostability, higher α helical content, and ability to reduce membrane fluidity and to adopt a distorted helix, bent in correspondence of Aib<sup>8</sup>. Overall, this study has shown how a strategic single amino acid substitution is sufficient to enlarge the spectrum of activity of the original peptide <b>1</b>, and improve its biological properties for therapeutic purposes, thus paving the way to optimize AMPs for the development of new broad-spectrum anti-infective agents.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Strategic Single-Residue Substitution in the Antimicrobial Peptide Esc(1-21) Confers Activity against <i>Staphylococcus aureus</i>, Including Drug-Resistant and Biofilm Phenotype.\",\"authors\":\"Maria Rosa Loffredo, Bruno Casciaro, Rosa Bellavita, Cassandra Troiano, Diego Brancaccio, Floriana Cappiello, Francesco Merlino, Stefania Galdiero, Giancarlo Fabrizi, Paolo Grieco, Lorenzo Stella, Alfonso Carotenuto, Maria Luisa Mangoni\",\"doi\":\"10.1021/acsinfecdis.4c00130\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><i>Staphylococcus aureus</i>, a bacterium resistant to multiple drugs, is a significant cause of illness and death worldwide. Antimicrobial peptides (AMPs) provide an excellent potential strategy to cope with this threat. Recently, we characterized a derivative of the frog-skin AMP esculentin-1a, Esc(1-21) (<b>1</b>) that is endowed with potent activity against Gram-negative bacteria but poor efficacy against Gram-positive strains. In this study, three analogues of peptide <b>1</b> were designed by replacing Gly<sup>8</sup> with α-aminoisobutyric acid (Aib), Pro, and dPro (<b>2</b>-<b>4</b>, respectively). The single substitution Gly<sup>8</sup> → Aib<sup>8</sup> in peptide <b>2</b> makes it active against the planktonic form of Gram-positive bacterial strains, especially <i>Staphylococcus aureus</i>, including multidrug-resistant clinical isolates, with an improved biostability without resulting in cytotoxicity to mammalian cells. Moreover, peptide <b>2</b> showed a higher antibiofilm activity than peptide <b>1</b> against both reference and clinical isolates of <i>S</i>. <i>aureus</i>. Peptide <b>2</b> was also able to induce rapid bacterial killing, suggesting a membrane-perturbing mechanism of action. Structural analysis of the most active peptide <b>2</b> evidenced that the improved biological activity of peptide <b>2</b> is the consequence of a combination of higher biostability, higher α helical content, and ability to reduce membrane fluidity and to adopt a distorted helix, bent in correspondence of Aib<sup>8</sup>. Overall, this study has shown how a strategic single amino acid substitution is sufficient to enlarge the spectrum of activity of the original peptide <b>1</b>, and improve its biological properties for therapeutic purposes, thus paving the way to optimize AMPs for the development of new broad-spectrum anti-infective agents.</p>\",\"PeriodicalId\":17,\"journal\":{\"name\":\"ACS Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-06-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsinfecdis.4c00130\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsinfecdis.4c00130","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Strategic Single-Residue Substitution in the Antimicrobial Peptide Esc(1-21) Confers Activity against Staphylococcus aureus, Including Drug-Resistant and Biofilm Phenotype.
Staphylococcus aureus, a bacterium resistant to multiple drugs, is a significant cause of illness and death worldwide. Antimicrobial peptides (AMPs) provide an excellent potential strategy to cope with this threat. Recently, we characterized a derivative of the frog-skin AMP esculentin-1a, Esc(1-21) (1) that is endowed with potent activity against Gram-negative bacteria but poor efficacy against Gram-positive strains. In this study, three analogues of peptide 1 were designed by replacing Gly8 with α-aminoisobutyric acid (Aib), Pro, and dPro (2-4, respectively). The single substitution Gly8 → Aib8 in peptide 2 makes it active against the planktonic form of Gram-positive bacterial strains, especially Staphylococcus aureus, including multidrug-resistant clinical isolates, with an improved biostability without resulting in cytotoxicity to mammalian cells. Moreover, peptide 2 showed a higher antibiofilm activity than peptide 1 against both reference and clinical isolates of S. aureus. Peptide 2 was also able to induce rapid bacterial killing, suggesting a membrane-perturbing mechanism of action. Structural analysis of the most active peptide 2 evidenced that the improved biological activity of peptide 2 is the consequence of a combination of higher biostability, higher α helical content, and ability to reduce membrane fluidity and to adopt a distorted helix, bent in correspondence of Aib8. Overall, this study has shown how a strategic single amino acid substitution is sufficient to enlarge the spectrum of activity of the original peptide 1, and improve its biological properties for therapeutic purposes, thus paving the way to optimize AMPs for the development of new broad-spectrum anti-infective agents.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.