Antisense-guided isolation and structure elucidation of pannomycin, a substituted cis-decalin from Geomyces pannorum.
Antisense-based screening strategies can be used to sensitize a microorganism and selectively detect inhibitors against a particular cellular target of interest. A strain of Staphylococcus aureus that generates an antisense RNA against SecA,a central member of the protein secretion machinery, has been used to screen for novel antibacterials. Possible inhibitors of the SecA ATP-ase were selected with a high-throughput, two-plate agar-based whole cell differential sensitivity screen. After screening a library of over 115 000 natural products extracts with the SecA antisense strain, an extract of Geomyces pannorum was identified as providing increased activity against the sensitized strain as compared with the wild-type control. Bioassay-guided isolation of the active component from this fungal extract provided a new cis-decalin secondary metabolite, which we have named pannomycin.
Parish
Craig A
CA
Merck Research Laboratories, Rahway, New Jersey 07065, USA. craig_parish@merck.com
de la Cruz
Mercedes
M
Smith
Scott K
SK
Zink
Deborah
D
Baxter
Jenny
J
Tucker-Samaras
Samantha
S
Collado
Javier
J
Platas
Gonzalo
G
Bills
Gerald
G
Díez
Maria Teresa
MT
Vicente
Francisca
F
Peláez
Fernando
F
Wilson
Kenneth
K
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001203:Ascomycota / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D026901:Membrane Transport Proteins; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D016372:RNA, Antisense / Q000235:genetics* / Q000378:metabolism; D000069816:SEC Translocation Channels; D000081416:SecA Proteins; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D009281:Naphthalenes; D016372:RNA, Antisense; D000069816:SEC Translocation Channels; C534923:pannomycin; D000251:Adenosine Triphosphatases; D000081416:SecA Proteins