Multiple Penicillin Binding Protein Profiles in Penicillin Resistant Pneumococci: Evidence for the Clonal Nature of Resistance Among Clinical Isolates

Abstract

Previous studies haven shown that penicillin resistance in pneumococci is a multigenic property that involves the accumulation of chromosomal mutations in the structural genes of penicillin binding proteins (PBPs), resulting in the greatly decreased reactivity of these proteins for beta-lactam antibiotics. We examined the patterns and affinities of PBPs in 1560 clinical isolates representing a wide range of MICs (from 0.005-16 μg/ml), serotypes, isolation dates and sites. The vast majority of penicillin-susceptible isolates showed a common, predictable pattern of five PBPs with high affinities for benzylpenicillin in the relative order of3> 1A>2A> IB >2B. In contrast, the PBP profiles became variable in strains for which MICs were >0.1 μg/ml and PBPs A, 2 A and 2B of these strains showed decreased penicillin affinity parallel to the increasing levels of antibiotic resistance. While resistant strains exhibited a variety of distinct PBP profiles, these were stable for each particular strain and it is suggested that clinical isolates sharing a common PBP profile may represent the progeny of a distinct mutant clone. Penicillin-resistant clinical isolates and genetic transformants showed profoundly altered cell wall stem peptides. Our data suggest that the decreased penicillin affinity of mutationally altered PBP’s results in such a distortion of the active sites that these PBPs also become altered in their reactivity toward their normal natural substrates. Successful expression of high level penicillin resistance in pneumococci may require the acquisition of auxiliary mutation(s) that assure a sufficient supply of the chemically unusual wall precursors needed for the synthesis of the cell wall in penicillin-resistant pneumococci.