Synthetic Mimics of Native Siderophores Disrupt Iron Trafficking in Acinetobacter baumannii

Many pathogenic bacteria biosynthesize and excrete small molecule metallophores, known as siderophores, that are used to extract ferric iron from host sources to satisfy nutritional need. Native siderophores are often structurally complex multidentate chelators that selectively form high-affinity octahedral ferric iron complexes with defined chirality recognizable by cognate protein receptors displayed on the bacterial cell surface. Simplified achiral analogues can serve as synthetically tractable siderophore mimics with potential utility as chemical probes and therapeutic agents to better understand and treat bacterial infections, respectively. Here, we demonstrate that synthetic spermidine-derived mixed ligand bis-catecholate monohydroxamate siderophores (compounds 1-3) are versatile structural and biomimetic analogues of two native siderophores, acinetobactin and fimsbactin, produced by Acinetobacter baumannii, a multidrug-resistant Gram-negative human pathogen. The metal-free and ferric iron complexes of the synthetic siderophores are growth-promoting agents of A. baumannii, while the Ga(III)-complexes are potent growth inhibitors of A. baumannii with MIC values <1 μM. The synthetic siderophores compete with native siderophores for uptake in A. baumannii and maintain comparable apparent binding affinities for ferric iron (K_Fe) and the siderophore-binding protein BauB (K_d). Our findings provide new insight to guide the structural fine-tuning of these compounds as siderophore-based therapeutics targeting pathogenic strains of A. baumannii.