The “Trojan horse” against antimicrobial resistance: Siderophore conjugates and public health

Herrera-Callo A.D.; Chávez-Morán M.R. · Farmacia Hospitalaria (2026) · DOI: 10.1016/j.farma.2026.04.013

Resumen

Objective: Antimicrobial resistance, particularly in carbapenemase-producing Enterobacterales such as KPC-type, represents a critical threat to public health in Latin America, associated with high mortality rates and increased healthcare costs. This systematic review aims to evaluate the therapeutic potential of siderophore-drug and siderophore-peptide conjugates against priority multidrug-resistant pathogens, including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, analyzing their efficacy, mechanisms of action, and implementation challenges. Method: A systematic search was conducted in PubMed, Scopus, and Web of Science databases up to August 2025, using key terms such as “siderophore conjugates”, “Trojan horse antibiotics”, “antimicrobial resistance”, and “Gram-negative bacteria”. Preclinical and clinical studies, reviews, and meta-analyses published between 2019 and 2025 were included, selecting 55 references based on relevance to the topic, currency, and methodological quality. This review corresponds to a narrative review with a systematic literature search, developed in accordance with PRISMA guidelines. Results: Siderophore conjugates, via the “Trojan horse” mechanism, effectively exploit bacterial iron uptake systems to deliver antimicrobial agents in a targeted manner. They overcome key resistance mechanisms such as β-lactamase production, porin alterations, and efflux pump activity, while reducing systemic toxicity and preserving commensal microbiota. Clinical evidence (e.g., cefiderocol) and preclinical studies confirm efficacy against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, with significant reductions in minimum inhibitory concentrations (MICs). However, critical challenges were identified: optimization of chemical stability and intracellular drug release, complexity in synthesis and industrial scaling under Good Manufacturing Practice (GMP) standards, and regulatory and logistical barriers in resource-limited settings. Conclusions: Siderophore conjugates offer a targeted therapeutic approach against multidrug-resistant pathogens by exploiting the bacteria's own iron-uptake systems. Available evidence ranges from clinical results with cefiderocol to preclinical developments with other platforms. Their application, however, faces challenges that span chemical optimization, manufacturing, regulation, and access in clinical settings.

Instituciones: Universidad Nacional de Frontera