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Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I.
Antimicrob Agents Chemother. 2012 Sep; 56(9):4662-70.AA

Abstract

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.

Authors+Show Affiliations

Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22710113

Citation

Therien, Alex G., et al. "Broadening the Spectrum of Β-lactam Antibiotics Through Inhibition of Signal Peptidase Type I." Antimicrobial Agents and Chemotherapy, vol. 56, no. 9, 2012, pp. 4662-70.
Therien AG, Huber JL, Wilson KE, et al. Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I. Antimicrob Agents Chemother. 2012;56(9):4662-70.
Therien, A. G., Huber, J. L., Wilson, K. E., Beaulieu, P., Caron, A., Claveau, D., Deschamps, K., Donald, R. G., Galgoci, A. M., Gallant, M., Gu, X., Kevin, N. J., Lafleur, J., Leavitt, P. S., Lebeau-Jacob, C., Lee, S. S., Lin, M. M., Michels, A. A., Ogawa, A. M., ... Miesel, L. (2012). Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I. Antimicrobial Agents and Chemotherapy, 56(9), 4662-70. https://doi.org/10.1128/AAC.00726-12
Therien AG, et al. Broadening the Spectrum of Β-lactam Antibiotics Through Inhibition of Signal Peptidase Type I. Antimicrob Agents Chemother. 2012;56(9):4662-70. PubMed PMID: 22710113.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I. AU - Therien,Alex G, AU - Huber,Joann L, AU - Wilson,Kenneth E, AU - Beaulieu,Patrick, AU - Caron,Alexandre, AU - Claveau,David, AU - Deschamps,Kathleen, AU - Donald,Robert G K, AU - Galgoci,Andrew M, AU - Gallant,Michel, AU - Gu,Xin, AU - Kevin,Nancy J, AU - Lafleur,Josiane, AU - Leavitt,Penny S, AU - Lebeau-Jacob,Christian, AU - Lee,Suzy S, AU - Lin,Molly M, AU - Michels,Anna A, AU - Ogawa,Aimie M, AU - Painter,Ronald E, AU - Parish,Craig A, AU - Park,Young-Whan, AU - Benton-Perdomo,Liliana, AU - Petcu,Mihai, AU - Phillips,John W, AU - Powles,Mary Ann, AU - Skorey,Kathryn I, AU - Tam,John, AU - Tan,Christopher M, AU - Young,Katherine, AU - Wong,Simon, AU - Waddell,Sherman T, AU - Miesel,Lynn, Y1 - 2012/06/18/ PY - 2012/6/20/entrez PY - 2012/6/20/pubmed PY - 2013/1/8/medline SP - 4662 EP - 70 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 56 IS - 9 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/22710113/Broadening_the_spectrum_of_β_lactam_antibiotics_through_inhibition_of_signal_peptidase_type_I_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=22710113 DB - PRIME DP - Unbound Medicine ER -