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This version was published on February 1, 2007
Journal of Biomolecular Screening, Vol. 12, No. 1, 100-105 (2007)
DOI: 10.1177/1087057106296484

A Novel Inhibitor of Mycobacterium tuberculosis Pantothenate Synthetase

E. Lucile White

Southern Research Institute, Birmingham, AL white{at}sri.org

Kristen Southworth

Larry Ross

Sara Cooley

Rachel B. Gill

Melinda Ingrum Sosa

Anna Manouvakhova

Lynn Rasmussen

Southern Research Institute, Birmingham, AL

Celia Goulding

Institute for Genomics and Proteomics, University of California, Los Angeles

David Eisenberg

Institute for Genomics and Proteomics and Department of Chemistry and Biochemistry, University of California, Los Angeles

Thomas M. Fletcher, III

Southern Research Institute, Birmingham, AL

Pantothenate synthetase (PS; EC 6.3.2.1), encoded by the panC gene, catalyzes the essential adenosine triphosphate (ATP)–dependent condensation of D-pantoate and ß-alanine to form pantothenate in bacteria, yeast, and plants; pantothenate is a key precursor for the biosynthesis of coenzyme A (CoA) and acyl carrier protein (ACP). Because the enzyme is absent in mammals and both CoA and ACP are essential cofactors for bacterial growth, PS is an attractive chemotherapeutic target. An automated high-throughput screen was developed to identify drugs that inhibit Mycobacterium tuberculosis PS. The activity of PS was measured spectrophotometrically through an enzymatic cascade involving myokinase, pyruvate kinase, and lactate dehydrogenase. The rate of PS ATP utilization was quantitated by the reduction of absorbance due to the oxidation of NADH to NAD+ by lactate dehydrogenase, which allowed for an internal control to detect interference from compounds that absorb at 340 nm. This coupled enzymatic reaction was used to screen 4080 compounds in a 96-well format. This discussion describes a novel inhibitor of PS that exhibits potential as an antimicrobial agent.

Key Words: pantothenate synthetase • Mycobacterium tuberculosis • high-throughput screen • antimicrobial


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