Siderophore–Porphyrin conjugates for bacteria-selective antimicrobial photodynamic therapy

Abstract

Targeted delivery of photosensitizers represents a key strategy for improving the selectivity and efficacy of antimicrobial photodynamic therapy (aPDT). Herein, we describe the synthesis and biological evaluation of siderophore-conjugated photosensitizers designed to exploit bacterial iron acquisition pathways. Four distinct photosensitizers—neutral porphyrin (TPP), cationic porphyrin (TMPyP), metalloporphyrin (PdTMPyP), and chlorin (Ce6)—were covalently linked to deferoxamine B (DFO), a clinically approved hydroxamate siderophore. The resulting conjugates retained their intrinsic photophysical properties while exhibiting iron-dependent antimicrobial activity against siderophore-utilizing pathogens. TMPyP-DFO (3) was determined as the best compound, demonstrating potent antimicrobial photodynamic activity against Staphylococcus aureus and Acinetobacter baumannii under iron-deficient conditions (MIC₅₀ = 6.3–12.5 µM) with low mammalian cytotoxicity (LC₅₀ = 146.6 µM). Neutral porphyrin- and chlorin-siderophore conjugates (1 and 2, respectively) demonstrated either poor activity or lack of selectivity. These findings validate the ‘Trojan horse’ delivery strategy—achieved through the conjugation of cationic porphyrins with siderophores—as a promising strategy for enhancing bacterial selectivity in aPDT.

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