A biological price of antibiotic resistance: major changes in the peptidoglycan structure of penicillin-resistant pneumococci.
Pneumococcal strains with greatly elevated levels of resistance to penicillin have by now been described with increasing frequency worldwide. The mechanism of antibiotic resistance in these strains involves the molecular remodeling of cell wall synthetic enzymes (penicillin binding proteins). We have now analyzed the peptidoglycan structures of 10 penicillin-susceptible and 10 penicillin-resistant clinical isolates (4 of intermediate and 6 of high level resistance) with a high-resolution HPLC technique. Cell wall peptidoglycan of the susceptible strains contained monomeric and oligomeric forms of primarily (70% or more) linear stem peptides with the sequence of L-Ala-D-iGln-L-Lys-D-Ala (where iGln is isoglutamine). In contrast, the major peptide species (70% or more) of resistant cell walls were abnormal branched-stem peptides carrying Ala-Ser or Ala-Ala dipeptides on the epsilon-amino groups of the stem peptide lysine residues. The structural alteration in the peptidoglycan was not related to serotype, date, or site of isolation but showed strong correlation with penicillin resistance and was cotransformed with high-level penicillin resistance during genetic transformation. We suggest that the remodeling of the active site of penicillin binding proteins in the resistant bacteria, which results in the reduced affinity for penicillin, also changes the substrate preference of these enzymes for the more hydrophobic branched peptides (instead of linear peptides) for cell wall synthesis.
Garcia-Bustos
J
J
Rockefeller University, New York, NY 10021.
Tomasz
A
A
D000595:Amino Acid Sequence; D002473:Cell Wall / Q000032:analysis; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010403:Penicillin Resistance / Q000235:genetics*; D010446:Peptide Fragments / Q000302:isolation & purification; D010457:Peptidoglycan / Q000235:genetics* / Q000302:isolation & purification; D012703:Serotyping; D013296:Streptococcus pneumoniae / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification
D010446:Peptide Fragments; D010457:Peptidoglycan