Phosphonopeptides as antibacterial agents: mechanism of action of alaphosphin.
The novel antibacterial peptide mimetic alaphosphin (l-alanyl-l-1-aminoethylphosphonic acid) selectively inhibited peptidoglycan biosynthesis in both gram-negative and gram-positive bacteria. It induced accumulation of uridine diphosphate-N-acetyl-muramyl-tripeptide in gram-positive organisms and significantly reduced the intracellular pool levels of d-alanine. Alaphosphin was actively transported into bacterial cells by stereospecific peptide permeases and was subsequently hydrolyzed by intracellular aminopeptidases to yield l-1-aminoethylphosphonic acid. This alanine mimetic rapidly accumulated inside susceptible cells to yield a concentration which was 100- to 1,000-fold in excess of that of the precursor peptide in the surrounding medium. In the case of susceptible gram-negative organisms, it was shown that 1-aminoethylphosphonic acid was incorporated into a metabolite which was tentatively identified as uridine diphosphate-N-acetylmuramyl-aminoethylphosphonate. The primary intracellular target site of 1-aminoethylphosphonic acid was alanine racemase (EC 5.1.1.1), which was reversibly and competitively inhibited in the gram-negative organisms Escherichia coli and Pseudomonas aeruginosa and irreversibly inhibited in a time-dependent manner in the gram-positive organisms Staphylococcus aureus and Streptococcus faecalis. A secondary target site could be uridine diphosphate-N-acetylmuramyl-l-alanine synthetase [EC 6.3.2.8(b)]. The mechanism of action of alaphosphin may be regarded as involving at least three stages: (i) active transport by peptide permeases; (ii) intracellular peptidase cleavage; and (iii) action of l-1-aminoethylphosphonate on alanine racemase.
D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000411:Alanine Racemase / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology*; D010748:Phosphopeptides / Q000378:metabolism / Q000494:pharmacology; D012329:RNA, Bacterial / Q000378:metabolism; D014530:Uridine Diphosphate / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D009943:Organophosphorus Compounds; D010748:Phosphopeptides; D012329:RNA, Bacterial; C006437:alafosfalin; D014530:Uridine Diphosphate; D000411:Alanine Racemase; D000409:Alanine