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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The alarming rise of antimicrobial resistance constitutes a critical global health challenge, threatening the efficacy of conventional antibiotic therapies. Despite this crisis, abandoning antibiotics is premature; instead, a deliberate integration of traditional and emerging antimicrobial approaches is urgently required. The worldwide proliferation of resistant pathogens reflects decades of monotherapy, inadequate stewardship, and the persistent expectation that each new drug class would resolve resistance crises. This review provides a comprehensive overview of the fundamental mechanisms underlying antibiotic action and bacterial resistance, including reduced membrane permeability, efflux pump activity, target modification, and enzymatic inactivation. Building on this foundation, a broad spectrum of innovative antimicrobial strategies designed to complement or enhance antibiotic efficacy was critically examined. These approaches include natural products with intrinsic antimicrobial properties, immunotherapy to modulate host defenses, and antimicrobial photodynamic therapy (aPDT), which utilizes light-activated photosensitizers to generate reactive oxygen species and achieve localized microbial destruction. Notably, aPDT can overcome bacterial resistance, thereby restoring antibiotic effectiveness. Light delivery to infection sites is feasible across nearly all anatomical locations, whether by direct application, fiber optics, or endoscopic methods. Additional promising modalities, such as bacteriophage therapy, metallic and metal-oxide nanoparticles, and antimicrobial peptides (AMPs), are discussed with respect to their mechanisms, advantages, and translational potential. Collectively, these strategies represent a paradigm shift from antibiotic replacement to antibiotic revival and potentiation. By integrating multidisciplinary approaches, it is possible to extend the lifespan of current antibiotics while developing more robust, resistance-resilient therapies. The evidence presented confirms that antibiotic therapy remains an essential component of antimicrobial treatment, provided that it is supported by innovative, complementary technologies. Abandoning antibiotic therapy at this stage is unwarranted.<\/jats:p>","DOI":"10.3390\/ijms27188331","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antimicrobial Strategies in the Era of Resistance: It Is Too Early to Give Up Antibiotic Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2978-7076","authenticated-orcid":false,"given":"Jennifer M.","family":"Soares","sequence":"first","affiliation":[{"name":"Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda","family":"Alves","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6063-904X","authenticated-orcid":false,"given":"Koteswara Rao","family":"Yerra","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thalita H. N.","family":"Lima","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"},{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, S\u00e3o Carlos 13566-590, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadim","family":"Younes","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate C.","family":"Blanco","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, S\u00e3o Carlos 13566-590, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4833-239X","authenticated-orcid":false,"given":"Vanderlei S.","family":"Bagnato","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"},{"name":"S\u00e3o Carlos Institute of Physics, University of S\u00e3o Paulo, S\u00e3o Carlos 13566-590, SP, Brazil"},{"name":"CPRIT Scholar in Cancer Research, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104656","DOI":"10.1016\/j.drudis.2026.104656","article-title":"Antibacterial PROTACs: The road ahead for next-generation antibiotics?","volume":"31","author":"Milelli","year":"2026","journal-title":"Drug Discov. 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