Involvement of a change in penicillin target and peptidoglycan structure in low-level resistance to beta-lactam antibiotics in Neisseria gonorrhoeae.
A penicillin-susceptible gonococcus and its low-level resistant penA transformant were examined with regard to their penicillin-binding proteins (PBPs) and their peptidoglycan structures. Treatment of the susceptible strain with its MIC of penicillin (0.01 microgram/ml) led to significant binding to PBPs 2 and 3 and a substantial decrease in the O-acetyl modification on the peptidoglycan. Peptidoglycan synthesis gradually ceased over an extended time. When the penA strain was treated with the same concentration of penicillin, only binding to PBP 3 was observed and there was no O-acetylation decrease, with continued peptidoglycan synthesis. This suggested that PBP 2 was the primary target in penicillin-susceptible gonococci and that this protein participated in the O-acetylation of peptidoglycan. Penicillin concentrations representing the MIC for the penA transformant (0.06 microgram/ml) caused significant binding to PBPs 1, 2, and 3 in the susceptible strain and PBPs 1 and 3 in the penA strain. In both strains the rate of peptidoglycan synthesis and the cross-linkage of the peptidoglycan made declined sharply, suggesting that significant inhibition of PBP 1 interfered with transpeptidation. A model for low-level resistance is proposed in which a decreased PBP 2 affinity leads to assumption of the role of primary target in the resistant transformant by PBP 1. The differences observed in peptidoglycan metabolism are a direct consequence of this change.
D000107:Acetylation; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D006602:Hexosyltransferases; D007700:Kinetics; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D009344:Neisseria gonorrhoeae / Q000187:drug effects*; D010400:Penicillin G / Q000378:metabolism; D010403:Penicillin Resistance; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000494:pharmacology*; D010457:Peptidoglycan / Q000032:analysis / Q000096:biosynthesis*; D010458:Peptidyl Transferases; D013329:Structure-Activity Relationship; D014169:Transformation, Bacterial
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D010457:Peptidoglycan; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D010400:Penicillin G