Resistance to β-lactam antibiotics and its mediation by the sensor domain of the transmembrane BlaR signaling pathway in Staphylococcus aureus

Dasantila Golemi-Kotra, Joo Young Cha, Samy O. Meroueh, Sergei B. Vakulenko, Shahriar Mobashery

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Staphylococci, a leading cause of infections worldwide, have devised two mechanisms for resistance to β-lactam antibiotics. One is production of β-lactamases, hydrolytic resistance enzymes, and the other is the expression of penicillin-binding protein 2a (PBP 2a), which is not susceptible to inhibition by β-lactam antibiotics. The β-lactam sensor-transducer (BlaR), an integral membrane protein, binds β-lactam antibiotics on the cell surface and transduces the information to the cytoplasm, where gene expression is derepressed for both β-lactamase and penicillin-binding protein 2a. The gene for the sensor domain of the sensor-transducer protein (BlaRS) of Staphylococcus aureus was cloned, and the protein was purified to homogeneity. It is shown that β-lactam antibiotics covalently modify the BlaRS protein. The protein was shown to contain the unusual carboxylated lysine that activates the active site serine residue for acylation by the β-lactam antibiotics. The details of the kinetics of interactions of the BlaRs protein with a series of β-lactam antibiotics were investigated. The protein undergoes acylation by β-lactam antibiotics with microscopic rate constants (k2) of 1-26 s-1, yet the deacylation process was essentially irreversible within one cell cycle. The protein undergoes a significant conformational change on binding with β-lactam antibiotics, a process that commences at the preacylation complex and reaches its full effect after protein acylation has been accomplished. These conformational changes are likely to be central to the signal transduction events when the organism is exposed to the β-lactam antibiotic.

Original languageEnglish (US)
Pages (from-to)18419-18425
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number20
DOIs
StatePublished - May 16 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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