Antimicrobial effects of novel siderophores linked to beta-lactam antibiotics

As a strategy to increase the penetration of antibiotic drugs through the o uter membrane of Gram-negative pathogens, facilitated transport through sid erophore receptors has been frequently exploited. Hydroxamic acids, catecho ls, or very close isosteres of catechols, which are mimics of naturally occ urring siderophores, have been used successfully as covalently linked escor ting moieties, but a much wider diversity of iron binding motifs exists. Th is observation, coupled to the relative lack of specificity of siderophore receptors, prompted us to initiate a program to identify novel, noncatechol siderophoric structures. We screened over 300 compounds for their ability to (1) support growth in low iron medium of a Pseudomonas aeruginosa sidero phore biosynthesis deletion mutant, or (2) compete with a bactericidal side rophore-antibiotic conjugate for siderophore receptor access. From these as says we identified a set of small molecules that fulfilled one or both of t hese criteria. We then synthesized these compounds with functional groups s uitable for attachment to both monobactam and cephalosporin core structures . Siderophore-P-lactam conjugates then were tested against a panel of Esche richia coli, Pseudomonas aeruginosa, and Staphylococcus aureus strains. Alt hough several of the resultant chimeric compounds had antimicrobial activit y approaching that of ceftazidime, and most compounds demonstrated very pot ent activity against their cellular targets, only a single compound was obt ained that had enhanced, siderophore-mediated antibacterial activity. Resul ts with tonB mutants frequently showed increased rather than decreased susc eptibilities, suggesting that multiple factors influenced the intracellular concentration of the drugs. (C) 2000 Elsevier Science Ltd. All rights rese rved.