Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors.
QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (-)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the beta subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.
Infectious Diseases Biology and Medicinal Chemistry, Pharmacia Corporation, 301 Henrietta St., Kalamazoo, Michigan 49001, USA. alita.a.miller@pfizer.com
Alita A
AA
Miller
Gordon L
GL
Bundy
John E
JE
Mott
Jill E
JE
Skepner
Timothy P
TP
Boyle
Douglas W
DW
Harris
Alexander E
AE
Hromockyj
Keith R
KR
Marotti
Gary E
GE
Zurenko
Jennifer B
JB
Munzner
Michael T
MT
Sweeney
Gary F
GF
Bammert
Judith C
JC
Hamel
Charles W
CW
Ford
Wei-Zhu
WZ
Zhong
David R
DR
Graber
Gary E
GE
Martin
Fusen
F
Han
Lester A
LA
Dolak
Eric P
EP
Seest
J Craig
JC
Ruble
Gregg M
GM
Kamilar
John R
JR
Palmer
Lee S
LS
Banitt
Alexander R
AR
Hurd
Michael R
MR
Barbachyn
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D001424:Bacterial Infections / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D008657:Metabolic Clearance Rate; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D059005:Topoisomerase II Inhibitors