SELECTIVE GROWTH PROMOTION AND GROWTH-INHIBITION OF GRAM-NEGATIVE ANDGRAM-POSITIVE BACTERIA BY SYNTHETIC SIDEROPHORE-BETA-LACTAM CONJUGATES

Conjugates of a carbacephalosporin with hydroxamate, spermexatol, N-al pha, N-epsilon-bis(2,3-dihydroxybenzoyl)-L-lysine, mixed catecholate/h ydroxamate and cyanuric acid-based siderophores were investigated for their potential to promote growth of siderophore indicator strains of Gram-negative and Gram-positive bacteria under iron depleted condition s, for their antibacterial activity and for their ability to use iron transport pathways to penetrate the Gram-negative bacterial outer memb rane. The selective growth promotion of enterobacterial and pseudomona s strains by hydroxamate, spermexatol and mixed catecholate-hydroxamat e siderophore-based conjugates bearing a L- or D-amino acid spacer was correlated with TonB dependent uptake routes. The preferred outer mem brane siderophore receptor used in Escherichia coli was found to be Fi u, followed by Cir. Antagonistic effects of siderophores administered with the conjugates to determine antibacterial activity confirmed the active transport of conjugates via siderophore receptors. All of the c onjugates were still able to diffuse through the porin proteins OmpC a nd OmpF. Nevertheless, strong inhibition of E. coli and Pseudomones ae ruginosa outer membrane mutants DC2 and K799/61 compared to the parent strains indicated inefficient penetrability of all types of conjugate s tested. Mycobacterium smegmatis SG 987 was able to use all of the si derophore-cephalosporin conjugates as growth promotors. Consequently t here was no growth inhibition of this strain.