Author:
Therien Alex G.,Huber Joann L.,Wilson Kenneth E.,Beaulieu Patrick,Caron Alexandre,Claveau David,Deschamps Kathleen,Donald Robert G. K.,Galgoci Andrew M.,Gallant Michel,Gu Xin,Kevin Nancy J.,Lafleur Josiane,Leavitt Penny S.,Lebeau-Jacob Christian,Lee Suzy S.,Lin Molly M.,Michels Anna A.,Ogawa Aimie M.,Painter Ronald E.,Parish Craig A.,Park Young-Whan,Benton-Perdomo Liliana,Petcu Mihai,Phillips John W.,Powles Mary Ann,Skorey Kathryn I.,Tam John,Tan Christopher M.,Young Katherine,Wong Simon,Waddell Sherman T.,Miesel Lynn
Abstract
ABSTRACTThe resistance of methicillin-resistantStaphylococcus 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 bothin vitroandin vivowith potent efficacy. Thein vitroactivity 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
71 articles.
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