Sökning: WFRF:(Das Anirban) > Assessment of Mycob...
Fältnamn | Indikatorer | Metadata |
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000 | 04175naa a2200613 4500 | |
001 | oai:DiVA.org:uu-229964 | |
003 | SwePub | |
008 | 140818s2014 | |||||||||||000 ||eng| | |
024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2299642 URI |
024 | 7 | a https://doi.org/10.1128/AAC.00140-142 DOI |
040 | a (SwePub)uu | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a ref2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Reddy, B. K. Kishore4 aut |
245 | 1 0 | a Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors |
264 | 1 | c 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 | 7 | a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe |
650 | 7 | a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng |
650 | 7 | a NATURVETENSKAPx Biologix Cellbiologi0 (SwePub)106042 hsv//swe |
650 | 7 | a NATURAL SCIENCESx Biological Sciencesx Cell Biology0 (SwePub)106042 hsv//eng |
700 | 1 | a Landge, Sudhir4 aut |
700 | 1 | a Ravishankar, Sudha4 aut |
700 | 1 | a Patil, Vikas4 aut |
700 | 1 | a Shinde, Vikas4 aut |
700 | 1 | a Tantry, Subramanyam4 aut |
700 | 1 | a Kale, Manoj4 aut |
700 | 1 | a Raichurkar, Anandkumar4 aut |
700 | 1 | a Menasinakai, Sreenivasaiah4 aut |
700 | 1 | a Mudugal, Naina Vinay4 aut |
700 | 1 | a Ambady, Anisha4 aut |
700 | 1 | a Ghosh, Anirban4 aut |
700 | 1 | a Tunduguru, Ragadeepthi4 aut |
700 | 1 | a Kaur, Parvinder4 aut |
700 | 1 | a Singh, Ragini4 aut |
700 | 1 | a Kumar, Naveen4 aut |
700 | 1 | a Bharath, Sowmya4 aut |
700 | 1 | a Sundaram, Aishwarya4 aut |
700 | 1 | a Bhat, Jyothi4 aut |
700 | 1 | a Sambandamurthy, Vasan K.4 aut |
700 | 1 | a Björkelid, Christoferu Uppsala universitet,Struktur- och molekylärbiologi4 aut0 (Swepub:uu)chbjo425 |
700 | 1 | a Jones, T. Alwynu Uppsala universitet,Struktur- och molekylärbiologi4 aut0 (Swepub:uu)alwyjone |
700 | 1 | a Das, Kaveri4 aut |
700 | 1 | a Bandodkar, Balachandra4 aut |
700 | 1 | a Malolanarasimhan, Krishnan4 aut |
700 | 1 | a Mukherjee, Kakoli4 aut |
700 | 1 | a Ramachandran, Vasanthi4 aut |
710 | 2 | a Uppsala universitetb Struktur- och molekylärbiologi4 org |
773 | 0 | t Antimicrobial Agents and Chemotherapyg 58:6, s. 3312-3326q 58:6<3312-3326x 0066-4804x 1098-6596 |
856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-229964 |
856 | 4 8 | u https://doi.org/10.1128/AAC.00140-14 |
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