[58] Formation of UDP-acetylmuramyl peptides

Ito, Eiji; Nathenson, Stanley G.; Dietzler, David N.; Anderson, John S.; Strominger, Jack L.

doi:10.1016/0076-6879(66)08062-5

Cited by 39 publications

(35 citation statements)

References 22 publications

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“…UDP-N-acetylmuramyl-L-ala~-D-glu-(L)-3H-meso-DAP was prepared by adding 3 H-meso-DAP to UDPNacetylmuramyl-L-ala-D-glu according to Ito et al [22] with the meso-DAP adding enzyme isolated from Corynebacterium xerosis ATCC 77 11. The compound was isolated from the reaction mixture by procedures A,B and A.…”

Section: Fieparation Of Substratesmentioning

confidence: 99%

Study of the N‐acetylmuramyl‐L‐alanine amidase activity in Escherichia coli

Heijenoort

1971

FEBS Letters

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Section: Fieparation Of Substratesmentioning

confidence: 99%

Study of the N‐acetylmuramyl‐L‐alanine amidase activity in Escherichia coli

Heijenoort

1971

FEBS Letters

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“…The standard muropeptide precursors uridine diphosphate-N-acetylmuramic acid (UDP-NAMA), UDP-NAMA-Ala, and UDP-NAMA-tri-and pentapeptides were obtained as previously described (12), and they were chemically identified by amino acid and hexosamine analysis and by Fourier-transform nuclear magnetic resonance.…”

Section: Methodsmentioning

confidence: 99%

Antibacterial activity and mechanism of action of phosphonopeptides based on aminomethylphosphonic acid

Atherton¹,

Hall²,

Hassall³

et al. 1982

Antimicrob Agents Chemother

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Phosphonopeptides based on aminomethylphosphonic acid as the C-terminal residue linked to L-amino acids possessed antibacterial activity in vitro and in vivo. Analogs in this series were generally less potent than corresponding compounds based on L-1-aminoethylphosphonic acid such as alafosfalin (L-alanyl-L-1-aminoethylphosphonic acid). Significant differences in antibacterial spectra were observed. The mechanism of action involved active transport of the peptide mimetics into the bacterial cells, followed by intracellular release of high concentrations of aminomethylphosphonic acid which inhibited bacterial cell wall biosynthesis. Aminomethylphosphonic acid behaved as a mimetic of both D-and L-alanine and inhibited D-Ala-D-Ala synthetase (EC 6.3.2.4.), alanine racemase (EC 5.1.1.1.), and UDP-N-acetylmuramyl-L-alanine synthetase (EC 6.3.2.8.). The minimal inhibitory concentration of L-norvalyl-aminomethylphosphonic acid was essentially unaffected by the presence of D-alanine, whereas the activity of the corresponding L-norvalyl derivative of L-1-aminoethylphosphonic acid was markedly decreased. Substantial differences in the inhibitory and lytic activity of the Lnorvalyl derivatives of aminomethylphosphonic and L-1-aminoethylphosphonic acids were also observed when these agents were combined with other inhibitors of bacterial cell wall biosynthesis.Previous papers have described results of investigations on the antibacterial properties of phosphonopeptides (1-7). Alafosfalin [L-alanyl-L-1-aminoethylphosphonic atid; L-Ala-L-Ala(P)] has been selected for clinical studies in humans. Other related compounds incorporating L-Ala(P) are of interest for particular applications in therapy.In these studies, phosphonopeptides with alternative aminoalkylphosphonic acid residues were investigated. Phosphonopeptides incorporating aminomethylphosphonic acid, Gly(P), were the only compounds with levels of antibacterial activity comparable with those of the L-

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“…The cell contents were released by heating at 100°C for 5 min, the precipitated material was removed by centrifugation, and the N-acetylhexosamine content was determined (24). Nucleotide-muropeptide precursors were separated from cell extracts by either charcoal adsorption (20 mg/,umol of nucleotide) followed by elution with water-NH3-ethanol (50:0.3:50) (14) or by ion-exchange chromatography on Dowex 1 (Cl-; AG1-X2) using a linear gradient of 0.01 to 0.4 M NaCl in 0.01 N HCl. After desalting on Sephadex G10 where necessary, the nucleotide fractions were further separated and characterized by descending chromatography on Whatman no.…”

mentioning

confidence: 99%

“…Standard muropeptide precursors were obtained from S. aureus as follows: uridine diphosphate-N-acetylmuramic acid (UDP-NAMA) was obtained by novobiocin treatment (33); UDP-NAMA-Ala was obtained by enzymic addition of L-['4C]alanine to UDP-NAMA (14); UDP-NAMA-tripeptide was obtained by D-cycloserine treatment; and UDP-NAMA-pentapeptide was obtained by vancomycin treatment (14).…”

mentioning

confidence: 99%

Phosphonopeptides as Antibacterial Agents: Mechanism of Action of Alaphosphin

Atherton

Hall

Hassall

et al. 1979

Antimicrob Agents Chemother

156

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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-alarnie. 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 Alaphosphin is representative of a novel series of antibacterial phosphonopeptides which was designed to mimnic the terminal dipeptide moiety (D-Ala-D-Ala) of bacterial cell wall peptidoglycan (2). Other papers (3, 5) have described the antibacterial properties of selected phosphonopeptides and have given some indication of structure-activity relationships in this series. Several points of evidence have suggested that transport into the bacterial cell is an important factor for activity. In this paper we describe investigations which confirm this and elucidate later stages in the mechanism of action of alaphosphin on typical bacteria. MATERIALS AND METHODSChemicals. Alaphosphin [Ala-Ala(P)] and L-and D-1-aminoethylphosphonic acids [Ala(P)] were prepared by the methods of Atherton et al. (5). '4C-labeled alaphosphin was prepared by R. J. Francis by using similar methods. All other radiochemicals were purchased from the Radiochemical Centre, Amersham, England. Chemicals were of analytical grade or equivalent and were purchased from either BDH

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[58] Formation of UDP-acetylmuramyl peptides

Cited by 39 publications

References 22 publications

Study of the N‐acetylmuramyl‐L‐alanine amidase activity in Escherichia coli

Study of the N‐acetylmuramyl‐L‐alanine amidase activity in Escherichia coli

Antibacterial activity and mechanism of action of phosphonopeptides based on aminomethylphosphonic acid

Phosphonopeptides as Antibacterial Agents: Mechanism of Action of Alaphosphin

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