Mycolic acid biosynthesis: definition and targeting of the Claisen condensation step.
Through the use of 2,2-[2H]palmitic acid pulse labeling of the whole cells of C. matruchotti and analysis by gas chromatography-mass spectrometry of the non-labeled and [2H]-labeled corynomycolates, we established a new mechanism for palmitate condensation devoid of the postulated carboxylation step. This evidence allowed the design and synthesis of several structurally related antagonists against the condensation reactions which were shown to possess potent in vivo activity against C. matruchotti with complete inhibition of growth on solid media at concentrations between 1-10 microg/ml. In addition, a cell-free in vitro assay of corynomycolate synthesis was developed to allow the screening of these and other antagonists.
Lee
R E
RE
Department of Microbiology, Colorado State University, Fort Collins 80523-1677, USA.
Armour
J W
JW
Takayama
K
K
Brennan
P J
PJ
Besra
G S
GS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003352:Corynebacterium / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D009171:Mycolic Acids / Q000378:metabolism* / Q000494:pharmacology; D010168:Palmitates / Q000737:chemistry / Q000494:pharmacology; D019308:Palmitic Acid / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009171:Mycolic Acids; D010168:Palmitates; C013898:corynomycolic acid; D019308:Palmitic Acid; D064429:Fatty Acid Synthases