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.