Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities.
Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.
Infectious Diseases, Merck Research Laboratories, Merck & Co., PO Box 2000, Rahway, NJ 07065, USA. sheo_singh@merck.com
Sheo B
SB
Singh
Michael A
MA
Goetz
Scott K
SK
Smith
Deborah L
DL
Zink
Jon
J
Polishook
Russell
R
Onishi
Scott
S
Salowe
Judyann
J
Wiltsie
John
J
Allocco
Janet
J
Sigmund
Karen
K
Dorso
Mercedes
M
de la Cruz
Jesús
J
Martín
Francisca
F
Vicente
Olga
O
Genilloud
Robert G K
RG
Donald
John W
JW
Phillips
D000192:Actinomycetales / Q000737:chemistry; D000617:Aminoglycosides / Q000302:isolation & purification* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009281:Naphthalenes / Q000302:isolation & purification* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D059005:Topoisomerase II Inhibitors; C580577:kibdelomycin A; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase