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.