Chloroalanyl antibiotic peptides: antagonism of their antimicrobial effects by L-alanine and L-alanyl peptides in gram-negative bacteria.
A large number of structurally diverse di- and tripeptides containing the alanine racemase inactivator beta-chloro-L-alanine (beta-Cl-LAla) have been synthesized, and their antibacterial properties in vitro have been evaluated. The dipeptides 1, 3-6, and 8-17 and the tripeptide 20 are all broad-spectrum antibacterial agents with considerable potency against both Gram-positive and Gram-negative species, but none of these peptides improves dramatically on the antibiotic efficacy of the previously described beta-Cl-LAla-beta-Cl-LAla, 9 (Cheung, K. S.; Wasserman, S. A.; Dudek, E.; Lerner, S. A.; Johnston, M. J. Med. Chem. 1983, 26, 1733). Gram-negative microorganisms, such as Escherichia coli, Hemophilus influenzae, Shigella flexneri, and Enterobacter species are consistently resistant to any haloalanyl peptide containing an alanyl residue, such as the dipeptide LAla-beta-Cl-LAla (2) and the tripeptides LMet-LAla-beta-Cl-LAla (7), LAla-LAla-beta-Cl-LAla (18), and LVal-LAla-beta-Cl-LAla (19). Correspondingly, these same organisms are protected from the bactericidal effects of 9 by supplementation of the growth medium with LAla or LAla-LAla. Escherichia coli JSR-O exposed to 9, but protected from lysis by sucrose stabilization, has only about 10% the normal level of intracellular alanine racemase activity. But when these cells are cultured in the presence of 9 with LAla supplementation, or in the presence of 2 with no supplementation, the alanine racemase levels are only about 20-30% below control values. These findings suggest that the resistance of Gram-negative species to chloroalanyl peptides containing alanyl units arises from the ability of LAla to protect the targeted racemase from inactivation by beta-Cl-LAla in vivo, an event which otherwise leads to cell death and lysis. Inactivation of alanine racemase in Gram-positive organisms appears not to be the cellular event that confers sensitivity of these species to a haloalanyl peptide.
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000411:Alanine Racemase / Q000037:antagonists & inhibitors*; D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D000637:Transaminases / Q000037:antagonists & inhibitors; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D009842:Oligopeptides; D015091:beta-Alanine; C002956:alanylalanine; C006977:3-chloroalanine; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase; D000591:Amino Acid Isomerases; D000411:Alanine Racemase; D000409:Alanine