Vancomycin, LY264826and four TV-substituted derivatives of LY264826were examined for dimerization, binding to D-alanyl-D-alanine-and D-alanyl-D-lactate-containing cell wall ligands, and binding to bacterial membranevesicles. The six glycopeptide antibiotics represent a 360-fold range in antibacterial activities against Micrococcus luteus (MIC = 0.00072~0.26 /im) with the N-substituted compounds having the lowest MICs. Vancomycin, LY264826 and the four TV-substituted derivatives
LY146032, a cyclic lipopeptide antibiotic, is an inhibitor of cell wall peptidoglycan biosynthesis in gram-positive bacteria. Although LY146032 at relatively high concentrations inhibited the in vitro polymerization of UDP-linked sugar precursors, inhibition of cell wall formation in intact Staphylococcus aureus and Bacillus megatetium cells did not lead to the accumulation of UDP-N-acetyl-muramyl (MurNAc)-peptide(s). Experiments that measured formation of UDP-MurNAc-peptides revealed that LY146032 inhibited the formation of these nucleotide-linked intermediates. This antibiotic had a disruptive effect on membrane permeability as evidenced by the loss of intracellular potassium immediately after exposure to the drug. The lack of any major disruption of the phosphoenolpyruvate:sugar phosphotransferase system indicated that the membrane is not likely a lethal target for this antibiotic. The findings are consistent with a mechanism by which LY146032 inhibits the formation of precursor molecules utilized in peptidoglycan biosynthesis. The observed membrane effects likely result from transit of the inhibitor to its lethal target site.
The UDP-MurNAc-pentapeptide is transferred to the outer face of the cell membrane by a lipid carrier and incorporated along with UDP-N-acetylglucosamine into the cell wall structure. The synthesis of other types of peptidoglycan precursors was demonstrated a few years ago in the context of several studies concerning vancomycin resistance. Vancomycin and other glycopeptide antibiotics can bind to the DAla-D-Ala terminus of pentapeptide-containing precursors by hydrogen bonding, thereby effectively blocking polymerization and preventing further cross-linking reactions (7, 41). Investigations of the molecular basis of vancomycin resistance started with strains of Enterococcus faecium and Enterococcus faecalis which showed inducible resistance to high levels of vancomycin and teicoplanin, another glycopeptide antibiotic. Examination of enzymes involved in cell wall synthesis in the resistant bacteria indicated that resistance to vancomycin was due to the synthesis of a novel type of peptidoglycan in which the terminal D-alanine residue was replaced by D-lactate, resulting in a drastic reduction of affinity for vancomycin (2,4,12,25,36). Two enzymes designated VanH and VanA are required for the synthesis of this alternative precursor (5). VanH is an ␣-ketoacid dehydrogenase that reduces pyruvate to D-lactate The synthesis of another type of peptidoglycan precursor has been described for Enterococcus gallinarum, which expresses inducible resistance to low levels of vancomycin but is susceptible to teicoplanin. In this case, the modified precursor terminates in D-serine instead of D-lactate (9). This feature results from the presence of another variant D-Ala-D-Ala ligase accepting D-serine (18).The genera Lactobacillus, Leuconostoc, and Pediococcus comprise strains and species constitutively resistant to vancomycin (15,20,33,39,46,49). Recently, peptidoglycan precursors from several of these lactic acid bacteria were analyzed. In Pediococcus pentosaceus and Lactobacillus casei (9, 26), the exclusive presence of a terminal D-lactate has been demonstrated. This presence could result from the action of a ligase which preferentially or exclusively catalyzes the synthesis of a D-Ala-D-Lac depsipeptide, as was suggested by Elisha and Courvalin (19). Analysis of Leuconostoc mesenteroides extracts identified a precursor that also terminates in D-lactate, but with an additional branched L-alanine In this paper, we report that the wild-type strain Lactobacillus plantarum NCIMB8826 is naturally resistant to high levels of vancomycin and teicoplanin and exclusively produces Dlactate-ending peptidoglycan precursors. We describe the construction of a strain defective for both D-and L-LDH, resulting in drastically reduced production of both isomers of lactate. We show that this alteration leads to the synthesis of a new type of precursor ending with D-alanine in addition to the usual muramyl depsipentapeptide observed in the wild-type strain,
Vancomycin resistance in Enterococcus faecium 180, a clinical isolate from England, was studied. Resistance to vancomycin was transferable by conjugation to other enterococci. Expression of resistance was inducible and coincided with the appearance of a new membrane protein.
A54145 complex is made up of eight factors; A, A1? B, B1? C, D, E, and F which were active in vitro (MIC 0.25~> 32/ig/ml) against Gram-positive aerobic organisms. The complex, factors B and Bj were found to be active against two strains of Clostridium perfringens. A calcium dependence study on someof the factors showed that their in vitro antibacterial activity was greatly enhanced by the presence of calcium (50mg/liter) in the media. Resistance build-up was seen when Staphylococcus sp. and Streptococcus sp. were passed seven times in the presence of sublethal concentrations of A54145antibiotics. This resistance disappeared immediately when the resistant organisms were passed in the absence of the antibiotics. Factor A was very effective against Staphylococcus aureus and Streptococcuspyogenes infections in mice (sc ED5Osof 3.3~2.4 mg/kg x 2, respectively). Factor B was more active against S. pyogenes in vivo (sc ED50, 0.9mg/kg x 2). Acute mousetoxicities were determined with these antibiotics. Semisynthetic derivatives were evaluated.
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