A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci.
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.
Zhang
H Z
HZ
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.
Hackbarth
C J
CJ
Chansky
K M
KM
Chambers
H F
HF
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D005809:Genes, Regulator; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D046915:Penicillin-Binding Proteins; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D014169:Transformation, Bacterial; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000096:biosynthesis*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D046915:Penicillin-Binding Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D047090:beta-Lactams; D008666:Metalloendopeptidases; D001618:beta-Lactamases