Among Gram-negative bacteria, P. aeruginosa is often involved in nosocomial infections (6.2% of infected hospitalized patients). P. aeruginosa belongs to first list of antibiotic-resistant “priority pathogens” described by the World Health Organization. We are interested in the development of new ways to combat this bacterium, targeted due to its high level of resistance to antibiotics via a lack of membrane permeability or efflux. Using iron transport systems is a promising Trojan Horse strategy to overcome these phenomena by restoring the activity of conventional antibiotics. Indeed, iron is a micronutrient necessary for the survival of bacteria. It is essential to many biological processes such as respiration, DNA synthesis… However, the ferric iron has a low bioavailability due to its low solubility in water. Under iron limited conditions, many bacteria synthesize molecules of low molecular weight called siderophores able to chelate the surrounding iron. According to their kind, bacteria express different types of outer membrane receptors (OMR) that recognize their endogenous siderophores but also xenosiderophores or synthetic siderophores. These specific systems may allow the introduction of antibacterial agents by forming siderophore-antibiotic conjugates. A proof of concept has already been established with the cefiderocol, an injectable catecholate-cephalosporin conjugate active against multidrug resistant strains of P. aeruginosa (MIC 0.5 µg.mL-1). Herein, we will describe the ciprofloxacin-based conjugate synthesis and their corresponding antipseudomonal activities. Our conjugates could be internalized into bacteria via the iron chelator moieties (catechol or hydroxypyridinone) linked to the antibiotic by a spacer, cleavable or not.

A trojan horse strategy: Synthesis and antipseudomonal activities of new iron chelator-ciprofloxacin conjugates

ACS Fall 2021

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