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The World Health Organization has established a priority list highlighting critical multidrug-resistant (MDR) pathogens that demand urgent research on antimicrobial treatments. Considering this and the fact that new antibiotics are only sporadically approved, natural antibacterial agents have seen a resurgence in interest as potential alternatives to conventional antibiotics and chemotherapeutics. Natural antibacterials, derived from microorganisms, higher fungi, plants, animals, natural minerals, and food sources, offer diverse mechanisms of action against MDR pathogens. Here, we present a comprehensive summary of antibacterial agents from natural sources, including a brief history of their application and highlighting key strategies for using microorganisms (microbiopredators, such as bacteriophages), plant extracts and essential oils, minerals (e.g., silver and copper), as well as compounds of animal origin, such as milk or even venoms. The review also addresses the role of prebiotics, probiotics, and antimicrobial peptides, as well as novel formulations such as nanoparticles. The mechanisms of action of these compounds, such as terpenoids, alkaloids, and phenolic compounds, are explored alongside the challenges for their application, e.g., extraction, formulation, and pharmacokinetics. Conclusions: Future research should focus on developing eco-friendly, sustainable antimicrobial agents and validating their safety and efficacy through clinical trials. Clear regulatory frameworks are essential for integrating these agents into clinical practice. Despite challenges, natural sources offer transformative potential for combating AMR and promoting sustainable health solutions.<\/jats:p>","DOI":"10.3390\/antibiotics14030253","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T05:52:16Z","timestamp":1740981136000},"page":"253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Nature\u2019s Arsenal: Uncovering Antibacterial Agents Against Antimicrobial Resistance"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1578-2776","authenticated-orcid":false,"given":"Ina","family":"Gajic","sequence":"first","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0327-4838","authenticated-orcid":false,"given":"Dusan","family":"Kekic","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5993-0577","authenticated-orcid":false,"given":"Marko","family":"Jankovic","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0086-0054","authenticated-orcid":false,"given":"Nina","family":"Tomic","sequence":"additional","affiliation":[{"name":"Group for Biomedical Engineering and Nanobiotechnology, Institute of Technical Sciences of SASA, Kneza Mihaila 35\/IV, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mila","family":"Skoric","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos","family":"Petrovic","sequence":"additional","affiliation":[{"name":"University Clinical Hospital Center \u201cDr. Dragisa Misovic-Dedinje\u201d, Heroja Milana Tepi\u0107a, 1, 11040 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6651-6814","authenticated-orcid":false,"given":"Dragana","family":"Mitic Culafic","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8765-4044","authenticated-orcid":false,"given":"Natasa","family":"Opavski","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petar","family":"Ristivojevic","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8794-9408","authenticated-orcid":false,"given":"Maja","family":"Krstic Ristivojevic","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojana","family":"Lukovic","sequence":"additional","affiliation":[{"name":"College of Health Sciences, Academy of Applied Studies Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Salam, M.A., Al-Amin, M.Y., Salam, M.T., Pawar, J.S., Akhter, N., Rabaan, A.A., and Alqumber, M.A.A. 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