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Science 291 (5510): 1962-1965

Copyright © 2001 by the American Association for the Advancement of Science

A Proteolytic Transmembrane Signaling Pathway and Resistance to beta -Lactams in Staphylococci

H. Z. Zhang, C. J. Hackbarth, K. M. Chansky, H. F. Chambers*

beta -Lactamase and penicillin-binding protein 2a mediate staphylococcal resistance to beta -lactam antibiotics, which are otherwise highly clinically effective. Production of these inducible proteins is regulated by a signal-transducing integral membrane protein and a transcriptional repressor. The signal transducer is a fusion protein with penicillin-binding and zinc metalloprotease domains. The signal for protein expression is transmitted by site-specific proteolytic cleavage of both the transducer, which autoactivates, and the repressor, which is inactivated, unblocking gene transcription. Compounds that disrupt this regulatory pathway could restore the activity of beta -lactam antibiotics against drug-resistant strains of staphylococci.

Division of Infectious Diseases, San Francisco General Hospital, Department of Medicine, University of California at San Francisco, 1001 Potrero Avenue, San Francisco, CA 94110, USA.
*   To whom correspondence should be addressed. E-mail: chipc{at}

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Y. Chen, F. C. Tenover, and T. M. Koehler (2004)
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Crystal Structures of the Apo and Penicillin-acylated Forms of the BlaR1 {beta}-Lactam Sensor of Staphylococcus aureus.
M. S. Wilke, T. L. Hills, H.-Z. Zhang, H. F. Chambers, and N. C. J. Strynadka (2004)
J. Biol. Chem. 279, 47278-47287
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Novel Non-mecA-Containing Staphylococcal Chromosomal Cassette Composite Island Containing pbp4 and tagF Genes in a Commensal Staphylococcal Species: a Possible Reservoir for Antibiotic Resistance Islands in Staphylococcus aureus.
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Antimicrob. Agents Chemother. 48, 1823-1836
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On the Transcriptional Regulation of Methicillin Resistance: MecI REPRESSOR IN COMPLEX WITH ITS OPERATOR.
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J. Biol. Chem. 279, 17888-17896
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Evidence of an Intramolecular Interaction between the Two Domains of the BlaR1 Penicillin Receptor during the Signal Transduction.
S. Hanique, M.-L. Colombo, E. Goormaghtigh, P. Soumillion, J.-M. Frere, and B. Joris (2004)
J. Biol. Chem. 279, 14264-14272
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PBP 2a Mutations Producing Very-High-Level Resistance to Beta-Lactams.
Y. Katayama, H.-Z. Zhang, and H. F. Chambers (2004)
Antimicrob. Agents Chemother. 48, 453-459
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R. Garcia-Castellanos, A. Marrero, G. Mallorqui-Fernandez, J. Potempa, M. Coll, and F. X. Gomis-Ruth (2003)
J. Biol. Chem. 278, 39897-39905
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Jumping the Barrier to {beta}-Lactam Resistance in Staphylococcus aureus.
Y. Katayama, H.-Z. Zhang, D. Hong, and H. F. Chambers (2003)
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Quantitation of mecA Transcription in Oxacillin-Resistant Staphylococcus aureus Clinical Isolates.
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Resistance to {beta}-Lactam Antibiotics and Its Mediation by the Sensor Domain of the Transmembrane BlaR Signaling Pathway in Staphylococcus aureus.
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J. Biol. Chem. 278, 18419-18425
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Dimerization and DNA Binding Properties of the Bacillus licheniformis 749/I BlaI Repressor.
P. Filee, C. Vreuls, R. Herman, I. Thamm, T. Aerts, P. P. De Deyn, J.-M. Frere, and B. Joris (2003)
J. Biol. Chem. 278, 16482-16487
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{beta}-Lactamase Genes of the Penicillin-Susceptible Bacillus anthracis Sterne Strain.
Y. Chen, J. Succi, F. C. Tenover, and T. M. Koehler (2003)
J. Bacteriol. 185, 823-830
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Biochemistry and Comparative Genomics of SxxK Superfamily Acyltransferases Offer a Clue to the Mycobacterial Paradox: Presence of Penicillin-Susceptible Target Proteins versus Lack of Efficiency of Penicillin as Therapeutic Agent.
C. Goffin and J.-M. Ghuysen (2002)
Microbiol. Mol. Biol. Rev. 66, 702-738
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Transcription of the Gene Mediating Methicillin Resistance in Staphylococcus aureus (mecA) Is Corepressed but Not Coinduced by Cognate mecA and beta -Lactamase Regulators.
T. K. McKinney, V. K. Sharma, W. A. Craig, and G. L. Archer (2001)
J. Bacteriol. 183, 6862-6868
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MICROBIOLOGY: Signaling Antibiotic Resistance in Staphylococci.
G. L. Archer and J. M. Bosilevac (2001)
Science 291, 1915-1916
   Full Text »
The Active 80S Ribosome-Sec61 Complex.
Cold Spring Harb Symp Quant Biol 66, 543-554
   Abstract »    PDF »

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