Siderophore Conjugates Leverage 'Trojan Horse' Mechanism to Combat Multidrug-Resistant Gram-Negative Bacteria

The escalating crisis of Antimicrobial Resistance (AMR), particularly from carbapenemase-producing Enterobacterales (e.g., KPC-type), poses a severe global public health threat, leading to high mortality and increased healthcare costs. Current standard-of-care antibiotics often fail due to bacterial resistance mechanisms like β-lactamase production, porin alterations, and efflux pump activity. There is an urgent need for novel therapeutic strategies that can bypass these defenses. Siderophore conjugates offer a promising approach by hijacking essential bacterial iron uptake systems, providing a targeted delivery mechanism for antimicrobial agents.

This systematic review evaluated the therapeutic potential of siderophore-drug and siderophore-peptide conjugates against priority multidrug-resistant pathogens. A comprehensive systematic search was conducted across PubMed, Scopus, and Web of Science databases up to August 2025. The review included 55 preclinical and clinical studies, reviews, and meta-analyses published between 2019 and 2025, selected based on relevance, currency, and methodological quality. The methodology adhered to PRISMA guidelines for a narrative review with a systematic literature search, analyzing efficacy, mechanisms of action, and implementation challenges.

Siderophore conjugates effectively utilize bacterial iron uptake systems, acting as a 'Trojan horse' to deliver antimicrobial agents directly into bacterial cells. This innovative strategy enables them to overcome critical resistance mechanisms, including β-lactamase production, porin alterations, and efflux pump activity, which are common in multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Clinical evidence, notably with cefiderocol, and numerous preclinical studies confirm significant efficacy against these challenging pathogens.

These conjugates achieve significant reductions in minimum inhibitory concentrations (MICs) while concurrently reducing systemic toxicity and preserving commensal microbiota. The review highlights their potent activity against carbapenemase-producing Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, which are critical threats in Latin America and globally. They demonstrate a targeted approach that minimizes off-target effects.