دورية
Broadening the Spectrum of β-Lactam Antibiotics through Inhibition of Signal Peptidase Type I
| العنوان: | Broadening the Spectrum of β-Lactam Antibiotics through Inhibition of Signal Peptidase Type I |
|---|---|
| المؤلفون: | 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 |
| المصدر: | Antimicrobial Agents and Chemotherapy; June 2012, Vol. 56 Issue: 9 p4662-4670, 9p |
| مستخلص: | ABSTRACTThe 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 vitroand in vivowith potent efficacy. The in 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00664804 10986596 |
|---|---|
| DOI: | 10.1128/AAC.00726-12 |