Selective growth promotion and growth inhibition of gram-negative and gram-positive bacteria by synthetic siderophore-beta-lactam conjugates.
Conjugates of a carbacephalosporin with hydroxamate, spermexatol, N alpha,N epsilon-bis(2,3-dihydroxybenzoyl)-L-lysine, mixed catecholate/hydroxamate 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 conditions, for their antibacterial activity and for their ability to use iron transport pathways to penetrate the Gram-negative bacterial outer membrane. The selective growth promotion of enterobacterial and pseudomonas strains by hydroxamate, spermexatol and mixed catecholate-hydroxamate siderophore-based conjugates bearing a L- or D-amino acid spacer was correlated with TonB dependent uptake routes. The preferred outer membrane siderophore receptor used in Escherichia coli was found to be Fiu, 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 conjugates were still able to diffuse through the porin proteins OmpC and OmpF. Nevertheless, strong inhibition of E. coli and Pseudomones aeruginosa outer membrane mutants DC2 and K799/61 compared to the parent strains indicated inefficient penetrability of all types of conjugates tested. Mycobacterium smegmatis SG 987 was able to use all of the siderophore-cephalosporin conjugates as growth promotors. Consequently there was no growth inhibition of this strain.
Möllmann
U
U
Hans-Knöll Institut für Naturstoff-Forschung, Jena, Germany. Mollmann@leutra.imb-jena.de
Ghosh
A
A
Dolence
E K
EK
Dolence
J A
JA
Ghosh
M
M
Miller
M J
MJ
Reissbrodt
R
R
D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001693:Biological Transport, Active; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology; D002511:Cephalosporins / Q000737:chemistry / Q000494:pharmacology*; D003864:Depression, Chemical; D029968:Escherichia coli Proteins; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000254:growth & development; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D009161:Mycobacterium / Q000187:drug effects / Q000254:growth & development; D017262:Siderophores / Q000737:chemistry / Q000494:pharmacology*; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013268:Stimulation, Chemical; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology
D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002396:Catechols; D002511:Cephalosporins; D029968:Escherichia coli Proteins; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D017262:Siderophores; D014227:Triazines; C026739:carbacephems; C057616:tonB protein, Bacteria; C489181:tonB protein, E coli; C058448:spermexatol; C041892:azotochelin; D007501:Iron; C004632:cyanuric acid; D008239:Lysine; D013095:Spermidine