Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I.
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.
Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
Alex G
AG
Therien
Joann L
JL
Huber
Kenneth E
KE
Wilson
Patrick
P
Beaulieu
Alexandre
A
Caron
David
D
Claveau
Kathleen
K
Deschamps
Robert G K
RG
Donald
Andrew M
AM
Galgoci
Michel
M
Gallant
Xin
X
Gu
Nancy J
NJ
Kevin
Josiane
J
Lafleur
Penny S
PS
Leavitt
Christian
C
Lebeau-Jacob
Suzy S
SS
Lee
Molly M
MM
Lin
Anna A
AA
Michels
Aimie M
AM
Ogawa
Ronald E
RE
Painter
Craig A
CA
Parish
Young-Whan
YW
Park
Liliana
L
Benton-Perdomo
Mihai
M
Petcu
John W
JW
Phillips
Mary Ann
MA
Powles
Kathryn I
KI
Skorey
John
J
Tam
Christopher M
CM
Tan
Katherine
K
Young
Simon
S
Wong
Sherman T
ST
Waddell
Lynn
L
Miesel
D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D047630:Depsipeptides / Q000302:isolation & purification / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006020:Glycopeptides / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D006027:Glycosides / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D055666:Lipopeptides / Q000302:isolation & purification / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D018440:beta-Lactam Resistance / Q000187:drug effects / Q000235:genetics; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001713:Biphenyl Compounds; D047630:Depsipeptides; D006020:Glycopeptides; D006027:Glycosides; D055666:Lipopeptides; C577089:M131 compound; D008565:Membrane Proteins; D009842:Oligopeptides; C577088:actinocarbasin; D047090:beta-Lactams; C577087:krisynomycin; D012697:Serine Endopeptidases; C026515:type I signal peptidase; D001618:beta-Lactamases