New aspects of the interplay between penicillin binding proteins, murM and the two component system CiaRH of penicillin-resistant Streptococcus pneumoniae serotype 19A isolates from Hungary [PublishAheadOfPrint]

The Streptococcus pneumoniae clone Hungary^19A-6 can expresses unusually high levels of β-lactam resistance which is in part due to mutations in the MurM gene encoding a transferase involved in the synthesis of branched peptidoglycan. Moreover it contains the allele ciaH232 encoding the histidine kinase CiaH (M Müller, P Marx, R Hakenbeck, and R Brückner, Microbiology 157:3104-12, 2011, doi: 10.1099/mic.0.053157-0). High-level penicillin resistance primarily requires the presence of low-affinity (mosaic) PBP genes as, for example, in strain Hu17, a closely related member of the Hungary^19A-6 lineage. Interestingly, strain Hu15, is β-lactam sensitive due to the absence of mosaic PBPs. This unique situation prompted us to investigate the development of cefotaxime resistance in transformation experiments with genes known to play a role in this phenotype: pbp2x, pbp1a, murM and ciaH, and the penicillin sensitive recipient strains R6 and Hu15. Characterization of phenotypes, peptidoglycan composition and CiaR-mediated gene expression revealed several novel aspects of penicillin resistance. The murM_Hu17 gene which is highly similar to murM of Streptococcus mitis induced morphological changes which were partly reversed by ciaH232. MurM_Hu17 conferred cefotaxime resistance only in the presence of pbp2x_Hu17. The ciaH232 allele contributed to a remarkable increase in cefotaxime resistance in combination with pbp2x_Hu17 and pbp1a_Hu17, accompanied with higher expression levels of CiaR regulated genes, documenting that ciaH232 responds to PBP1a_Hu17 mediated changes in cell wall synthesis. Most importantly, the proportion of branched over linear muropeptides increased in cells containing mosaic PBPs suggesting an altered enzymatic activity of these proteins.

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