SwePub
Sök i LIBRIS databas

  Extended search

onr:"swepub:oai:DiVA.org:uu-229964"
 

Search: onr:"swepub:oai:DiVA.org:uu-229964" > Assessment of Mycob...

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist

Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

Reddy, B. K. Kishore (author)
Landge, Sudhir (author)
Ravishankar, Sudha (author)
show more...
Patil, Vikas (author)
Shinde, Vikas (author)
Tantry, Subramanyam (author)
Kale, Manoj (author)
Raichurkar, Anandkumar (author)
Menasinakai, Sreenivasaiah (author)
Mudugal, Naina Vinay (author)
Ambady, Anisha (author)
Ghosh, Anirban (author)
Tunduguru, Ragadeepthi (author)
Kaur, Parvinder (author)
Singh, Ragini (author)
Kumar, Naveen (author)
Bharath, Sowmya (author)
Sundaram, Aishwarya (author)
Bhat, Jyothi (author)
Sambandamurthy, Vasan K. (author)
Björkelid, Christofer (author)
Uppsala universitet,Struktur- och molekylärbiologi
Jones, T. Alwyn (author)
Uppsala universitet,Struktur- och molekylärbiologi
Das, Kaveri (author)
Bandodkar, Balachandra (author)
Malolanarasimhan, Krishnan (author)
Mukherjee, Kakoli (author)
Ramachandran, Vasanthi (author)
show less...
 (creator_code:org_t)
2014
2014
English.
In: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 58:6, s. 3312-3326
Related links:
https://urn.kb.se/re...
show more...
https://doi.org/10.1...
show less...
  • Journal article (peer-reviewed)
Abstract Subject headings
Close  
  • 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.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Publication and Content Type

ref (subject category)
art (subject category)

Find in a library

To the university's database

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Close

Copy and save the link in order to return to this view