Premium
Mutations in the essential FAS II β‐hydroxyacyl ACP dehydratase complex confer resistance to thiacetazone in M ycobacterium tuberculosis and M ycobacterium kansasii
Author(s) -
Belardinelli Juan M.,
Morbidoni Héctor R.
Publication year - 2012
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.12005
Subject(s) - mycolic acid , dehydratase , biology , biochemistry , mycobacterium tuberculosis , biosynthesis , microbiology and biotechnology , mutant , enzyme , complementation , mycobacterium , acyl carrier protein , bacteria , tuberculosis , gene , genetics , medicine , pathology
Summary It has recently been shown that the anti‐mycobacterial pro‐drug thiacetazone ( TAC ) inhibits the conversion of double bonds of mycolic acid precursors into cyclopropyl rings in M ycobacterium bovis var BCG , M . marimum and M . chelonae by affecting the cyclopropyl mycolic acid synthases ( CMASs ) as judged by the build‐up of unsaturated mycolate precursors. In our hands, TAC inhibits mycolic acid biosynthesis in M ycobacterium tuberculosis and M . kansasii with almost negligible accumulation of those precursors. Our observations that ‘ de novo ’ biosynthesis of all the mycolic acid families decreased upon TAC treatment prompted us to analyse the role of each one of the T ype II F atty A cid S ynthase ( FASII ) enzymes. Overexpression of the hadABC operon, encoding the essential FASII dehydratase complex, but not of any of the remaining FASII genes acting on the elongation of fatty acyl chains leading to the synthesis of meromycolic acids, resulted in high level of resistance to TAC in M . tuberculosis . Spontaneous M . tuberculosis and M . kansasii TAC ‐resistant mutants isolated during this work revealed mutations in the hadABC genes strongly supporting our proposal that these enzymes are new players in the resistance to this anti‐mycobacterial compound.