Broadening the Spectrum of β-Lactam Antibiotics through Inhibition of Signal Peptidase Type I

Autor: John W. Phillips, Xin Gu, Mihai Petcu, Molly M. Lin, Ronald E. Painter, Michel Gallant, Lynn Miesel, Kathryn Skorey, Kenneth E. Wilson, David Claveau, Liliana L. Benton-Perdomo, Kathleen Deschamps, Christopher M. Tan, Katherine Young, Andrew Galgoci, John Tam, Christian Lebeau-Jacob, Alexandre Caron, Young-Whan Park, Suzy Lee, Simon Wong, Patrick Beaulieu, Craig A. Parish, Aimie M. Ogawa, Josiane Lafleur, Alex G. Therien, Nancy J. Kevin, Sherman T. Waddell, Robert G. K. Donald, Penny Sue Leavitt, Mary Ann Powles, Joann Huber, Anna A. Michels
Rok vydání: 2012
Předmět:
Methicillin-Resistant Staphylococcus aureus
Imipenem
Lipoglycopeptide
medicine.drug_class
Antibiotics
Microbial Sensitivity Tests
Biology
beta-Lactams
medicine.disease_cause
beta-Lactam Resistance
beta-Lactamases
Microbiology
Lipopeptides
Mice
chemistry.chemical_compound
Bacterial Proteins
Depsipeptides
polycyclic compounds
medicine
Animals
Humans
Experimental Therapeutics
Pharmacology (medical)
Glycosides
Pharmacology
Depsipeptide
Mice
Inbred BALB C
Signal peptidase
Biphenyl Compounds
Serine Endopeptidases
Glycopeptides
Membrane Proteins
Biological Transport
Drug Synergism
Staphylococcal Infections
biochemical phenomena
metabolism
and nutrition
bacterial infections and mycoses
Methicillin-resistant Staphylococcus aureus
Anti-Bacterial Agents
Biphenyl compound
Infectious Diseases
chemistry
Staphylococcus aureus
Multigene Family
Drug Therapy
Combination
Female
Oligopeptides
medicine.drug
Zdroj: Antimicrobial Agents and Chemotherapy. 56:4662-4670
ISSN: 1098-6596
0066-4804
DOI: 10.1128/aac.00726-12
Popis: The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem both in vitro and in vivo with potent efficacy. The in vitro activity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to β-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with β-lactams by preventing the signal peptidase-mediated secretion of proteins required for β-lactam resistance. Combinations of SpsB inhibitors and β-lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to β-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections.
Databáze: OpenAIRE
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