Resurgence of tuberculosis (TB) and other mycobacterial infections associated with AIDS threaten human health world-wide. Emergence of drug resistant TB makes it critical to discover new drug targets. Cell walls of Mycobacterium tuberculosis contain a variety of unusual lipids with many types of multiple methyl-branched fatty acids that are unique to pathogenic mycobacteria. These lipids are thought to play important roles in the ability of the pathogens to resist antimicrobial agents and evade the defense reactions of the host. Biosynthesis of these unique lipids containing multiple methyl-branched fatty acids could offer ideal targets for new anti mycobacterial drugs. Genomic sequencing revealed that a remarkably unique feature of the mycobacterial genome is that it contains an unusually large number of genes involved in lipid metabolism. Based on the homology to mycocerosic acid synthase (mas) we have identified two classes of polyketide synthase (pks)-like genes which contain a full complement of active site domains that should be involved in the catalysis of all of the steps required for the synthesis of multimethyl- branched fatty acids: Class 1 mas-like genes mas-like genes (msl1, msl2 and msl3) that are highly homologous to mas and Class 2 (msl4m msl5, msl6 and msl7) which show a lesser degree of homology to mas. These open reading frames (ORFs) most probably encode the more than eight classes of methyl-branched fatty acids found in M. tuberculosis. To elucidate the function of these genes and to examine their possible role in the host-pathogen interaction, we propose to pursue the following specific aims: 1) Determine the functions of Class 1 mas-like genes, ms1, msl2 and msl3 of M. tuberculosis by characterization of their products expressed in M. smegmatis, and by determination of the biochemical and functional consequences of their disruption. 2) Determine the functions of Class 2 (msl4, msl5, msl6 and msl7) mas-like genes in M. tuberculosis genome, by characterization of their products expressed in M. smegmatis, and by determination of the biochemical and functional consequences of their disruption. 3) Determine whether lack of specific lipids caused by the above gene-disruptions affects host-pathogen interaction and virulence. The results will help identify cell wall lipids critical for pathogenesis that might be suitable targets for new anti-mycobacterial drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI046582-04
Application #
6626371
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
2000-01-15
Project End
2003-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
4
Fiscal Year
2003
Total Cost
$300,066
Indirect Cost
Name
University of Central Florida
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
Daniel, Jaiyanth; Kapoor, Nidhi; Sirakova, Tatiana et al. (2016) The perilipin-like PPE15 protein in Mycobacterium tuberculosis is required for triacylglycerol accumulation under dormancy-inducing conditions. Mol Microbiol 101:784-94
Daniel, Jaiyanth; Sirakova, Tatiana; Kolattukudy, Pappachan (2014) An acyl-CoA synthetase in Mycobacterium tuberculosis involved in triacylglycerol accumulation during dormancy. PLoS One 9:e114877
Sirakova, Tatiana D; Deb, Chirajyoti; Daniel, Jaiyanth et al. (2012) Wax ester synthesis is required for Mycobacterium tuberculosis to enter in vitro dormancy. PLoS One 7:e51641
Daniel, Jaiyanth; Oh, Tae-Jin; Lee, Chang-Muk et al. (2007) AccD6, a member of the Fas II locus, is a functional carboxyltransferase subunit of the acyl-coenzyme A carboxylase in Mycobacterium tuberculosis. J Bacteriol 189:911-7
Lee, Kil-Soo; Dubey, Vinod S; Kolattukudy, Pappachan E et al. (2007) Diacyltrehalose of Mycobacterium tuberculosis inhibits lipopolysaccharide- and mycobacteria-induced proinflammatory cytokine production in human monocytic cells. FEMS Microbiol Lett 267:121-8
Sirakova, Tatiana D; Dubey, Vinod S; Deb, Chirajyoti et al. (2006) Identification of a diacylglycerol acyltransferase gene involved in accumulation of triacylglycerol in Mycobacterium tuberculosis under stress. Microbiology 152:2717-25
Cardona, P-J; Soto, C Y; Martin, C et al. (2006) Neutral-red reaction is related to virulence and cell wall methyl-branched lipids in Mycobacterium tuberculosis. Microbes Infect 8:183-90
Oh, Tae-Jin; Daniel, Jaiyanth; Kim, Hwa-Jung et al. (2006) Identification and characterization of Rv3281 as a novel subunit of a biotin-dependent acyl-CoA Carboxylase in Mycobacterium tuberculosis H37Rv. J Biol Chem 281:3899-908
Deb, Chirajyoti; Daniel, Jaiyanth; Sirakova, Tatiana D et al. (2006) A novel lipase belonging to the hormone-sensitive lipase family induced under starvation to utilize stored triacylglycerol in Mycobacterium tuberculosis. J Biol Chem 281:3866-75
Daniel, Jaiyanth; Deb, Chirajyoti; Dubey, Vinod S et al. (2004) Induction of a novel class of diacylglycerol acyltransferases and triacylglycerol accumulation in Mycobacterium tuberculosis as it goes into a dormancy-like state in culture. J Bacteriol 186:5017-30

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