Alland D

References (2)

Title : Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis - Wilson_2013_Nat.Chem.Biol_9_499
Author(s) : Wilson R , Kumar P , Parashar V , Vilcheze C , Veyron-Churlet R , Freundlich JS , Barnes SW , Walker JR , Szymonifka MJ , Marchiano E , Shenai S , Colangeli R , Jacobs WR, Jr. , Neiditch MB , Kremer L , Alland D
Ref : Nat Chemical Biology , 9 :499 , 2013
Abstract : We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis by the previously uncharacterized mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser55 site in Pks13 conferred TP resistance in M. tuberculosis. Overexpression of wild-type Pks13 resulted in TP resistance, and overexpression of the Pks13(F79S) mutant conferred high resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type M. tuberculosis, but it did so to a much lesser extent in TP-resistant M. tuberculosis. TP treatment was bactericidal and equivalent to treatment with the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment resulted in sterilizing activity. Computational docking identified a possible TP-binding groove within the Pks13 acyl carrier protein domain. This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.
ESTHER : Wilson_2013_Nat.Chem.Biol_9_499
PubMedSearch : Wilson_2013_Nat.Chem.Biol_9_499
PubMedID: 23770708
Gene_locus related to this paper: myctu-PKS13

Title : Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains - Fleischmann_2002_J.Bacteriol_184_5479
Author(s) : Fleischmann RD , Alland D , Eisen JA , Carpenter L , White O , Peterson J , Deboy R , Dodson R , Gwinn M , Haft D , Hickey E , Kolonay JF , Nelson WC , Umayam LA , Ermolaeva M , Salzberg SL , Delcher A , Utterback T , Weidman J , Khouri H , Gill J , Mikula A , Bishai W , Jacobs Jr WR, Jr. , Venter JC , Fraser CM
Ref : Journal of Bacteriology , 184 :5479 , 2002
Abstract : Virulence and immunity are poorly understood in Mycobacterium tuberculosis. We sequenced the complete genome of the M. tuberculosis clinical strain CDC1551 and performed a whole-genome comparison with the laboratory strain H37Rv in order to identify polymorphic sequences with potential relevance to disease pathogenesis, immunity, and evolution. We found large-sequence and single-nucleotide polymorphisms in numerous genes. Polymorphic loci included a phospholipase C, a membrane lipoprotein, members of an adenylate cyclase gene family, and members of the PE/PPE gene family, some of which have been implicated in virulence or the host immune response. Several gene families, including the PE/PPE gene family, also had significantly higher synonymous and nonsynonymous substitution frequencies compared to the genome as a whole. We tested a large sample of M. tuberculosis clinical isolates for a subset of the large-sequence and single-nucleotide polymorphisms and found widespread genetic variability at many of these loci. We performed phylogenetic and epidemiological analysis to investigate the evolutionary relationships among isolates and the origins of specific polymorphic loci. A number of these polymorphisms appear to have occurred multiple times as independent events, suggesting that these changes may be under selective pressure. Together, these results demonstrate that polymorphisms among M. tuberculosis strains are more extensive than initially anticipated, and genetic variation may have an important role in disease pathogenesis and immunity.
ESTHER : Fleischmann_2002_J.Bacteriol_184_5479
PubMedSearch : Fleischmann_2002_J.Bacteriol_184_5479
PubMedID: 12218036
Gene_locus related to this paper: myctu-a85a , myctu-a85b , myctu-a85c , myctu-bpoC , myctu-d5yk66 , myctu-ephA , myctu-ephB , myctu-ephc , myctu-ephd , myctu-ephE , myctu-ephF , myctu-hpx , myctu-linb , myctu-lipG , myctu-LPQP , myctu-MBTB , myctu-metx , myctu-mpt51 , myctu-MT3441 , myctu-p71654 , myctu-p95011 , myctu-PKS6 , myctu-PKS13 , myctu-ppe42 , myctu-ppe63 , myctu-Rv1430 , myctu-RV0045C , myctu-Rv0077c , myctu-Rv0151c , myctu-Rv0152c , myctu-Rv0159c , myctu-Rv0160c , myctu-rv0183 , myctu-Rv0217c , myctu-Rv0220 , myctu-Rv0272c , myctu-RV0293C , myctu-RV0421C , myctu-RV0457C , myctu-RV0519C , myctu-RV0774C , myctu-RV0782 , myctu-RV0840C , myctu-Rv1069c , myctu-Rv1076 , myctu-RV1123C , myctu-Rv1184c , myctu-Rv1190 , myctu-Rv1191 , myctu-RV1192 , myctu-RV1215C , myctu-Rv1399c , myctu-Rv1400c , myctu-RV1639C , myctu-RV1683 , myctu-RV1758 , myctu-Rv1800 , myctu-Rv1833c , myctu-Rv2045c , myctu-RV2054 , myctu-Rv2284 , myctu-RV2296 , myctu-Rv2385 , myctu-Rv2485c , myctu-RV2627C , myctu-RV2672 , myctu-RV2695 , myctu-RV2765 , myctu-RV2800 , myctu-RV2854 , myctu-Rv2970c , myctu-Rv3084 , myctu-Rv3097c , myctu-rv3177 , myctu-Rv3312c , myctu-RV3452 , myctu-Rv3487c , myctu-Rv3569c , myctu-Rv3591c , myctu-RV3724 , myctu-Rv3802c , myctu-Rv3822 , myctu-y0571 , myctu-y963 , myctu-Y1834 , myctu-y1835 , myctu-y2079 , myctu-Y2307 , myctu-yc88 , myctu-ym23 , myctu-ym24 , myctu-YR15 , myctu-yt28