Effects of the Vibrio cholerae siderophore vibriobactin on the growth characteristics of L1210 cells

Abstract

The microbial iron chelator vibriobactin, N-[3-(2,3-dihydroxybenzamido)propyl]-1,3-bis[2-(2, 3-dihydroxyphenyl)-trans-5-methyl-2-oxazoline-4-carboxamido]-propane, is shown to inhibit the growth of L1210 cells in culture, with an IC50 value of 2 microM. Its biological activity is assigned to the ligand's ability to chelate iron as indicated by the disappearance of its antimitotic properties on iron chelate preformation or on O-methylation. The ligand is shown to have pronounced effects on cell cycle kinetics introducing a G1/S phase block. When treated cells are washed free of the ligand with fresh media they cascade into a high S phase in 5 hrs. Furthermore, after exposure of L1210 cells to vibriobactin (10 microM) for 5 hrs followed by removal of the drug, cells display different doubling times relative to untreated controls, with lower bromodeoxyuridine (BrdUrd) incorporation and no apparent cell death as shown by a 51Cr release assay. The effects on cell kinetics are consistent with inhibition of ribonucleotide reductase. Finally, vibriobactin is also shown to be active with a human Burkitt lymphoma cell line (Daudi).