{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:37:37Z","timestamp":1790174257208,"version":"4.1.0"},"reference-count":332,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-45-10015"],"award-info":[{"award-number":["24-45-10015"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["24-45-10015"],"award-info":[{"award-number":["24-45-10015"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The escalating crisis of antibiotic resistance and the inherent limitations of conventional antibiotics necessitate the development of innovative therapeutic strategies. Targeted drug delivery (TDD) offers a powerful approach to enhance efficacy, minimize systemic toxicity, and circumvent bacterial resistance. This systematic review aims to evaluate the potential of unique bacterial transport systems (BTSs), surface specific receptors and intracellular enzymes as platforms for TDD via the \u201cTrojan Horse\u201d strategy (THS). Methods: A comprehensive literature review was conducted, focusing on studies that investigated the specificity and mechanisms of BTSs responsible for the uptake of metabolites that are essential for and unique to bacteria. This includes an analysis of transport systems for siderophores, bacteria-specific sugars, cell wall components, D-amino acids, and vitamins. We assessed preclinical and clinical examples of drug conjugates utilizing these pathways, as well as emerging platforms such as bacteriophage-derived proteins, antibody\u2013antibiotic conjugates, and bacterial extracellular vesicles (EVs). Results: BTSs demonstrate high specificity for their cognate substrates, providing effective molecular gateways for TDD of drugs photosensitizers and diagnostic probes in form of conjugates. The siderophore\u2013cephalosporin conjugate cefiderocol represents a clinically validated example, having received FDA approval. Preclinical studies further reveal that conjugates utilizing sugars (e.g., maltose, trehalose) and vitamins (e.g., B12) can significantly enhance antibiotic uptake and activity against both Gram-positive and Gram-negative pathogens, including drug-resistant strains. Emerging platforms like bacteriophage endolysins and engineered EVs show promise for overcoming biological barriers such as bacterial outer membranes and intracellular host niches. Conclusions: The THS leveraging BTSs represents a clinically viable and promising avenue for next-generation antibacterial therapies. Advantages of BTS include overcoming bacterial resistance, such as reduced membrane permeability and efflux pumps, enabling the \u201crevival\u201d of antibiotics that are poorly permeable or toxic, increasing their local concentration at the target site and reducing side effects on host cells. While significant progress has been made, a striking disconnect persists between the hundreds of conjugates demonstrating potent in vitro activity and the limited agent that has achieved clinical use. This in vitro\u2013in vivo gap reflects, in large part, the early stage of this field rather than a fundamental failure. Further research is critically needed not only to identify novel BTSs and optimize drug-linker chemistry, but also to systematically address the translational barriers\u2014including poor pharmacokinetics, immunogenicity, and unexpected toxicity\u2014that have prevented most promising candidates from advancing beyond preclinical evaluation.<\/jats:p>","DOI":"10.3390\/ph19050701","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Perspective Approaches to \u201cTrojan Horse\u201d Strategy Development for Combating Bacterial Pathogens"],"prefix":"10.3390","volume":"19","author":[{"given":"Margarita","family":"Shleeva","sequence":"first","affiliation":[{"name":"A.N. Bach Institute of Biochemistry, Federal Research Centre \u2018Fundamentals of Biotechnology\u2019, Russian Academy of Sciences, 119071 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8331-5818","authenticated-orcid":false,"given":"Nataliya","family":"Kozobkova","sequence":"additional","affiliation":[{"name":"A.N. Bach Institute of Biochemistry, Federal Research Centre \u2018Fundamentals of Biotechnology\u2019, Russian Academy of Sciences, 119071 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Demina","sequence":"additional","affiliation":[{"name":"A.N. Bach Institute of Biochemistry, Federal Research Centre \u2018Fundamentals of Biotechnology\u2019, Russian Academy of Sciences, 119071 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arseny","family":"Kaprelyants","sequence":"additional","affiliation":[{"name":"A.N. Bach Institute of Biochemistry, Federal Research Centre \u2018Fundamentals of Biotechnology\u2019, Russian Academy of Sciences, 119071 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e24655","DOI":"10.1002\/jcla.24655","article-title":"Antibiotic Resistance: The Challenges and Some Emerging Strategies for Tackling a Global Menace","volume":"36","author":"Ugwu","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Konstantinidis, T., Tsigalou, C., Karvelas, A., Stavropoulou, E., Voidarou, C., and Bezirtzoglou, E. (2020). Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature. 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