Transfer of penicillin resistance from Streptococcus oralis to Streptococcus pneumoniae identifies murE as resistance determinant

Mol Microbiol. 2015 Sep;97(5):866-80. doi: 10.1111/mmi.13070. Epub 2015 Jun 19.


Beta-lactam resistant clinical isolates of Streptococcus pneumoniae contain altered penicillin-binding protein (PBP) genes and occasionally an altered murM, presumably products of interspecies gene transfer. MurM and MurN are responsible for the synthesis of branched lipid II, substrate for the PBP catalyzed transpeptidation reaction. Here we used the high-level beta-lactam resistant S. oralis Uo5 as donor in transformation experiments with the sensitive laboratory strain S. pneumoniae R6 as recipient. Surprisingly, piperacillin-resistant transformants contained no alterations in PBP genes but carried murEUo5 encoding the UDP-N-acetylmuramyl tripeptide synthetase. Codons 83-183 of murEUo5 were sufficient to confer the resistance phenotype. Moreover, the promoter of murEUo5 , which drives a twofold higher expression compared to that of S. pneumoniae R6, could also confer increased resistance. Multiple independent transformations produced S. pneumoniae R6 derivatives containing murEUo5 , pbp2xUo5 , pbp1aUo5 and pbp2bUo5 , but not murMUo5 sequences; however, the resistance level of the donor strain could not be reached. S. oralis Uo5 harbors an unusual murM, and murN is absent. Accordingly, the peptidoglycan of S. oralis Uo5 contained interpeptide bridges with one L-Ala residue only. The data suggest that resistance in S. oralis Uo5 is based on a complex interplay of distinct PBPs and other enzymes involved in peptidoglycan biosynthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / genetics*
  • Drug Resistance, Multiple, Bacterial / genetics
  • Penicillin Resistance / genetics*
  • Penicillin-Binding Proteins / genetics
  • Peptide Synthases / genetics
  • Peptidoglycan / biosynthesis
  • Peptidoglycan / chemistry
  • Peptidoglycan / genetics
  • Peptidyl Transferases / genetics
  • Piperacillin / metabolism
  • Streptococcus oralis / drug effects*
  • Streptococcus oralis / genetics*
  • Streptococcus pneumoniae / drug effects*
  • Streptococcus pneumoniae / genetics*
  • Transformation, Genetic*
  • beta-Lactams / metabolism


  • Bacterial Proteins
  • Penicillin-Binding Proteins
  • Peptidoglycan
  • beta-Lactams
  • Peptidyl Transferases
  • Peptide Synthases
  • UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase
  • Piperacillin