{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:42:56Z","timestamp":1785426176427,"version":"3.56.0"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Coordena\u00e7\u00e3o de Aperfeicoamento de Pessoal de N\u00edvel Superior"},{"id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004809","name":"Financiadora de Estudos e Projetos","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004809","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/030w99567","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005668","name":"Funda\u00e7\u00e3o de Apoio \u00e0 Pesquisa do Distrito Federal","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005668","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04c807f09","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Funda\u00e7\u00e3o de Apoio ao Desenvolvimento do Ensino, Ci\u00eancia e Tecnologia do Mato Grosso do Sul"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: Cyclotides are plant-derived macrocyclic peptides distinguished by their head-to-tail cyclized backbone and cystine knot motif, which confer remarkable stability against thermal, enzymatic, and chemical degradation. These features, combined with a compact and rigid structure, position cyclotides as promising scaffolds for future antibacterial agents in response to the escalating threat of multidrug-resistant (MDR) pathogens and the stagnation of conventional antibiotic discovery pipelines. This review summarizes the structural features, antibacterial mechanisms, bioengineering strategies, and translational potential of cyclotides against MDR infections. Methods: A narrative review of the literature was conducted using recent original research articles and reviews on cyclotide structure, antibacterial activity, bioengineering, computational modeling, and pharmaceutical applications. Results: Cyclotides exhibit potent antimicrobial activity, primarily through membrane disruption mediated by amphipathic surfaces and affinity for anionic bacterial membranes. Some variants also demonstrate anti-virulence and antibiofilm properties, broadening their therapeutic relevance for difficult-to-treat infections. Bioengineering approaches, including epitope grafting and rational design, have improved selectivity and potency while reducing cytotoxicity. Advances in computational modeling, molecular dynamics, and artificial intelligence have accelerated the prediction and optimization of antimicrobial activity, toxicity, and pharmacokinetic properties. Conclusions: Innovations in synthesis, including recombinant expression and enzymatic ligation, are helping overcome translational barriers related to cost and scalability. Although challenges remain in oral bioavailability and systemic delivery, strategies such as lipidation and scaffold modification support the development of cyclotide-based therapeutics as adaptable platforms for peptide drug discovery.<\/jats:p>","DOI":"10.3390\/antibiotics15060604","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:49:01Z","timestamp":1781570941000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclotides from Plants Driving the Next Generation of Antibacterial Agents"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3126-029X","authenticated-orcid":false,"given":"Elizabete de Souza","family":"C\u00e2ndido","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Gen\u00f4micas e Biotecnologia, Universidade Cat\u00f3lica de Bras\u00edlia, Brasilia 71966-700, Brazil"},{"name":"S-Inova Biotech, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biotecnologia, Universidade Cat\u00f3lica Dom Bosco, Campo Grande 79117-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1035-3363","authenticated-orcid":false,"given":"Liryel Silva","family":"Gasparetto","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Gen\u00f4micas e Biotecnologia, Universidade Cat\u00f3lica de Bras\u00edlia, Brasilia 71966-700, Brazil"},{"name":"S-Inova Biotech, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biotecnologia, Universidade Cat\u00f3lica Dom Bosco, Campo Grande 79117-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5889-6984","authenticated-orcid":false,"given":"Mariana Rocha","family":"Maximiano","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Gen\u00f4micas e Biotecnologia, Universidade Cat\u00f3lica de Bras\u00edlia, Brasilia 71966-700, Brazil"},{"name":"S-Inova Biotech, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biotecnologia, Universidade Cat\u00f3lica Dom Bosco, Campo Grande 79117-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1730-2561","authenticated-orcid":false,"given":"Thuanny Borba","family":"Rios","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Gen\u00f4micas e Biotecnologia, Universidade Cat\u00f3lica de Bras\u00edlia, Brasilia 71966-700, Brazil"},{"name":"S-Inova Biotech, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biotecnologia, Universidade Cat\u00f3lica Dom Bosco, Campo Grande 79117-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9546-0525","authenticated-orcid":false,"given":"Oct\u00e1vio Luiz","family":"Franco","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Gen\u00f4micas e Biotecnologia, Universidade Cat\u00f3lica de Bras\u00edlia, Brasilia 71966-700, Brazil"},{"name":"S-Inova Biotech, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biotecnologia, Universidade Cat\u00f3lica Dom Bosco, Campo Grande 79117-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100962","DOI":"10.1016\/j.lanmic.2024.100962","article-title":"Antibacterial agents in preclinical and clinical development","volume":"5","author":"Jesudason","year":"2024","journal-title":"Lancet Microbe"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.mib.2017.05.014","article-title":"Next-generation precision antimicrobials: Towards personalized treatment of infectious diseases","volume":"37","author":"Torres","year":"2017","journal-title":"Curr. 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