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LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00004175naa a2200613 4500
001oai:DiVA.org:uu-229964
003SwePub
008140818s2014 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2299642 URI
0247 a https://doi.org/10.1128/AAC.00140-142 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Reddy, B. K. Kishore4 aut
2451 0a Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors
264 1c 2014
338 a print2 rdacarrier
520 a Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by the coaA gene is an essential pantothenate kinase in Mycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-type M. tuberculosis strain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in a M. tuberculosis knockdown strain with reduced PanK expression levels. Additionally, in vitro and in vivo survival kinetic studies performed with a M. tuberculosis PanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK in M. tuberculosis.
650 7a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng
650 7a NATURVETENSKAPx Biologix Cellbiologi0 (SwePub)106042 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciencesx Cell Biology0 (SwePub)106042 hsv//eng
7001 a Landge, Sudhir4 aut
7001 a Ravishankar, Sudha4 aut
7001 a Patil, Vikas4 aut
7001 a Shinde, Vikas4 aut
7001 a Tantry, Subramanyam4 aut
7001 a Kale, Manoj4 aut
7001 a Raichurkar, Anandkumar4 aut
7001 a Menasinakai, Sreenivasaiah4 aut
7001 a Mudugal, Naina Vinay4 aut
7001 a Ambady, Anisha4 aut
7001 a Ghosh, Anirban4 aut
7001 a Tunduguru, Ragadeepthi4 aut
7001 a Kaur, Parvinder4 aut
7001 a Singh, Ragini4 aut
7001 a Kumar, Naveen4 aut
7001 a Bharath, Sowmya4 aut
7001 a Sundaram, Aishwarya4 aut
7001 a Bhat, Jyothi4 aut
7001 a Sambandamurthy, Vasan K.4 aut
7001 a Björkelid, Christoferu Uppsala universitet,Struktur- och molekylärbiologi4 aut0 (Swepub:uu)chbjo425
7001 a Jones, T. Alwynu Uppsala universitet,Struktur- och molekylärbiologi4 aut0 (Swepub:uu)alwyjone
7001 a Das, Kaveri4 aut
7001 a Bandodkar, Balachandra4 aut
7001 a Malolanarasimhan, Krishnan4 aut
7001 a Mukherjee, Kakoli4 aut
7001 a Ramachandran, Vasanthi4 aut
7102 a Uppsala universitetb Struktur- och molekylärbiologi4 org
7730 t Antimicrobial Agents and Chemotherapyg 58:6, s. 3312-3326q 58:6<3312-3326x 0066-4804x 1098-6596
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-229964
8564 8u https://doi.org/10.1128/AAC.00140-14

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