Structural characterization of an abnormally cross-linked muropeptide dimer that is accumulated in the peptidoglycan of methicillin- and cefotaxime-resistant mutants of Staphylococcus aureus.
Laboratory mutants of Staphylococcus aureus strain ATCC 8325 (27S) selected for increased minimal inhibitory concentration (MIC) values to methicillin and cefotaxime showed increased rates of cell wall turnover and detergent-induced autolysis in virtual parallel with the increasing MIC for the antibiotic. Also in parallel with the increasing MICs for the particular antibiotic used in the selection was the gradual accumulation of an unusual muropeptide in the peptidoglycan of the mutants, muropeptide 12, which is a minor component of the cell wall of the parental strain. Analysis of muropeptide 12, its peptide derivative, and its lysostaphin degradation products by high pressure liquid chromatography, Edman degradation, and mass spectrometry suggests that muropeptide 12 is a dimer in which the two monomeric components are interlinked by two pentaglycyl cross-bridges, thus generating a 14-member macrocyclic ring structure. This unusual cross-linked structure may be the product of the abnormal activity of penicillin-binding protein 2 which has grossly reduced antibiotic binding capacity in the mutant staphylococci.
Boneca
I G
IG
Laboratory of Microbiology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Xu
N
N
Gage
D A
DA
de Jonge
B L
BL
Tomasz
A
A
D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002439:Cefotaxime / Q000494:pharmacology; D019281:Dimerization; D004352:Drug Resistance, Microbial / Q000235:genetics; D006602:Hexosyltransferases / Q000737:chemistry* / Q000378:metabolism; D016106:Methicillin Resistance; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism; D002267:Muramoylpentapeptide Carboxypeptidase; D009154:Mutation; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D001426:Bacterial Proteins; D002352:Carrier Proteins; D009097:Multienzyme Complexes; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D002439:Cefotaxime