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Antimicrobial resistance (AMR) is closely linked to the excessive and indiscriminate use of antibiotics, which creates selective pressure and promotes the emergence of resistant pathogens. Objectives: This study evaluates the synergistic potential of intragenic antimicrobial peptides (IAPs) combined with plant alkaloids against susceptible and multidrug-resistant human pathogenic bacteria, assessing antimicrobial activity, biofilm inhibition, and hemocompatibility. Methods: The tested molecules included berberine, tomatidine, sinomenine, and the IAPs Hs02 and Gr01. Minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) assays were performed against both ATCC (E. coli ATCC 25922 and S. aureus ATCC 25923) and clinical strains (E. coli KPC+ HRAN 1812446 and S. aureus MDR LACEN 3730529). Synergistic interactions were evaluated by checkerboard assay, followed by biofilm inhibition and hemolysis assays using human red blood cells. Results: Berberine exhibited a MIC of 1024 \u00b5M when tested individually, while tomatidine and sinomenine showed no significant activity. As expected, the IAPs showed strong antimicrobial properties at 8 \u00b5M (Hs02) and 4 \u00b5M (Gr01). When tested in synergy, alkaloids and IAPs reduced the MIC by up to 128-fold. The combination of IAPs and alkaloids reduced the biofilm biomass of S. aureus and E. coli by 50%, by the crystal violet assay (p &lt; 0.05). Notably, sinomenine had not previously been reported to have antimicrobial activity. Conclusions: These results highlight the importance of further exploring combinations of natural and synthetic bioactive molecules as promising antimicrobial candidates. This approach may help to extend the useful life of conventional antibiotics. However, further studies are needed to assess safety, cytotoxicity, genotoxicity, inflammation, and in vivo effects.<\/jats:p>","DOI":"10.3390\/antibiotics15060561","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:37:26Z","timestamp":1780454246000},"page":"561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synergistic Potential of Plant Alkaloids and Intragenic Antimicrobial Peptides in Treating Multidrug-Resistant Infectious Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4378-9681","authenticated-orcid":false,"given":"Athamy Sarah de Paula","family":"Cruz","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, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5163-0625","authenticated-orcid":false,"given":"Tha\u00eds Campos","family":"de Sousa","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, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3034-8699","authenticated-orcid":false,"given":"Nat\u00e1lia Elisabeth","family":"Kruklis","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, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilton Araripe dos Santos","family":"Neto","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Patologia Molecular, Universidade de Bras\u00edlia, Brasilia 70910-000, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca Oliveira do Vale","family":"Lira","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, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Rocha","family":"de Andrade","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, DF, 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, DF, Brazil"},{"name":"S-Inova Biotech, Programa de P\u00f3s-Gradua\u00e7\u00e3o, Universidade Cat\u00f3lica Dom Bosco, Campo Grande 79117-900, MS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1615-0009","authenticated-orcid":false,"given":"Guilherme Dotto","family":"Brand","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00edntese e An\u00e1lise de Biomol\u00e9culas, Instituto de Qu\u00edmica, Universidade de Bras\u00edlia, Brasilia 70910-000, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Henrique Soller","family":"Ramada","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, DF, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Gerontologia, Universidade Cat\u00f3lica de Bras\u00edlia, Brasilia 71966-700, DF, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022). 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