IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Insights on the Molecular Events that Unleash Resistance to beta-lactam antibiotics in Staphylococcus aureus
Autor/es:
LLARRULL, L.I.
Lugar:
Villa Carlos Paz
Reunión:
Congreso; XLII Reunion Anual de la Sociedad Argentina de Biofisica; 2013
Institución organizadora:
Sociedad Argentina de Biofisica
Resumen:
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.