Insights on the Molecular Events that Unleash Resistance to beta-lactam antibiotics in Staphylococcus aureus

LLARRULL, L.I.

Villa Carlos Paz

Congreso; XLII Reunion Anual de la Sociedad Argentina de Biofisica; 2013

Sociedad Argentina de Biofisica

Staphylococcus aureus is the main cause of hospital- and community-associated infections.1 The expression of the BlaZ beta-lactamase and of the PBP2a DD-transpeptidase renders S. aureus resistant to beta-lactam antibiotics. The expression of these gens is regulated by two related systems, composed of a membrane associated sensor protein (BlaR1 or MecR1, respectively) and a repressor (BlaI or MecI, respectively). The sensor proteins and PBP2a itself are promising targets for the design of inhibitors that would restore the efficiency of beta-lactam antibiotics. We have used a combination of spectroscopic techniques, biochemical techniques, molecular modeling and organic chemistry to characterize different aspects of these two systems. We have documented a lysine N-decarboxylation switch that arrests the sensor domain of BlaR1 in an activated state required for signal transduction,2,3 we have characterized BlaI binding to its operator region, and we have shown that the in vivo concentrations account for the basal level transcription of the resistance genes.4 We have also presented evidence that support the hypothesis that BlaR1 fragmentation is a means for turnover,5 a process required for recovery from induction of resistance in S. aureus in the absence of the antibiotic challenge, and that BlaR1 is indeed a metallo-protease that degrades the gene repressor BlaI.6 Regarding the DD-transpeptidase PBP2a, we have recently reported the identification of an allosteric binding site that regulates the opening of the active site to permit substrate entry, through a multiresidue conformational change.7 In my group, we are currently working on the elucidation of the topology and structure of the sensor proteins BlaR1 and MecR1.     Acknowledgements: The PEW Charitable Trusts, NIH, ANPCyT, CONICETReferences: 1 ? Llarrull LI, Fisher JF, Mobashery S. Antimicrob. Agents Chemother. 2009. 4051. 2 ? Borbulevych O, Kumarasiri M, Wilson B, Llarrull LI, et al. J. Biol. Chem. 2011. 31466 3 ? Kumarasiri M, Llarrull LI, et al. Journal of Biological Chemistry. 2012. 8232. 4 ? Llarrull LI, Prorok M, Mobashery S. Biochemistry. 2010. 7975 5 ? Llarrull LI, Toth M, Champion MM, Mobashery S. Journal of Biological Chemistry. 2011. 38148 6 ? Llarrull LI, Mobashery S. Biochemistry, 2012. 4642. 7 ? Otero LH, Rojas-Altuve A, Llarrull LI, et al. Proc. Natl. Acad. Sci. USA. 2013. 16808.