Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate beta-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we demonstrate these agents inhibit peptidoglycan synthesis. Because SAV1754 is essential for growth and structurally related to the recently reported peptidoglycan flippase of Escherichia coli, we speculate it performs an analogous function in S. aureus. These results suggest that SAV1754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.
Huber
Joann
J
Department of Infectious Diseases, Merck & Co., Rahway, NJ 07065, USA.
Donald
Robert G K
RG
Lee
Sang Ho
SH
Jarantow
Lisa Wang
LW
Salvatore
Michael J
MJ
Meng
Xin
X
Painter
Ronald
R
Onishi
Russell H
RH
Occi
James
J
Dorso
Karen
K
Young
Katherine
K
Park
Young Whan
YW
Skwish
Stephen
S
Szymonifka
Michael J
MJ
Waddell
Tim S
TS
Miesel
Lynn
L
Phillips
John W
JW
Roemer
Terry
T
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D016372:RNA, Antisense / Q000378:metabolism
C545732:2-(2-chlorophenyl)-3-(1-(2,3-dimethylbenzyl)piperidin-4-yl)-5-fluoro-1H-indole; C545731:3-(1-((2,3-dimethylphenyl)methyl)piperidin-4-yl)-1-methyl-2-pyridin-4-yl-1H-indole; D000900:Anti-Bacterial Agents; D015780:Carbapenems; D007211:Indoles; D010457:Peptidoglycan; D010880:Piperidines; D016372:RNA, Antisense