title: Resistance determinants for beta-lactam antibiotics in laboratory mutants of Streptococcus pneumoniae that are involved in genetic competence.
abstract: Laboratory mutants of Streptococcus pneumoniae resistant to either cefotaxime or piperacillin reveal defects in competence development independent of the selective beta-lactam. A resistance determinant ciaH encoding a putative histidine kinase of a two-component signal-transducing system that is also involved in competence regulation was recently identified in cefotaxime-resistant mutants. We show now that the CiaH protein can be phosphorylated by ATP in vitro, and that it also phosphorylates the cognate response regulator CiaR. The mutant C306 containing the CiaH mutation Thr-230-Pro is completely noncompetent. It does not release competence-inducing activity (competence factor) into the medium nor can such an activity be released from the cells. Competence in C306 cannot be induced upon addition of external competence factor, in contrast to the competence-defective piperacillin-resistant mutants P506 and P408. A novel resistance determinant cpoA specific for piperacillin was identified in piperacillin-resistant mutants. CpoA is responsible for the competence defect in P506 but not in P408. The results document a tight link between the action of beta-lactams and competence development in the pneumococcus and confirm that the two beta-lactams piperacillin and cefotaxime act via different primary targets.
authors.affiliation: Max-Planck Institut für molekulare Genetik, Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Zähner
authors.forename: T
authors.initials: T
authors.lastname: Grebe
authors.forename: E
authors.initials: E
authors.lastname: Guenzi
authors.forename: J
authors.initials: J
authors.lastname: Krauss
authors.forename: M
authors.initials: M
authors.lastname: van der Linden
authors.forename: K
authors.initials: K
authors.lastname: Terhune
authors.forename: J B
authors.initials: JB
authors.lastname: Stock
authors.forename: R
authors.initials: R
authors.lastname: Hakenbeck
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003001:Cloning, Molecular; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D000071677:Histidine Kinase; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D018440:beta-Lactam Resistance / Q000235:genetics*; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D011494:Protein Kinases; D000071677:Histidine Kinase