Elucidation of PanK Vulnerability in M. tuberculosis
V, Mukherjee K, Sambandamurthy V, Sharma UK. 2010. Essentiality
and functional analysis of type I and type III pantothenate kinases of
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dium. However, the broth experiments could be conducted
only for a maximum of 15 days (for reasons of cell clumping),
during which the PanK levels may not have become depleted
below critical levels. In addition, under conditions where the
strain exists in a nearly nonreplicating phase in an animal
model, reduction in CoA levels could be very minimal and
hence would explain the recovery of M. tuberculosis even after
long periods in vivo. The vulnerability studies, both genetic and
chemical, reported here demonstrate that PanK is not an attractive
antimycobacterial target. This is similar to the data observed in
earlier studies with a ⌬panCD M. tuberculosis strain (29), wherein
the auxotrophic mutant persisted in the lungs and spleens of in-
fected mice for over 6 months following intravenous infection.
Since PanCD and PanK are both enzymes from the CoA biosyn-
thetic pathway, the observations from this study and the earlier
⌬panCD report suggest the possible poor vulnerability of targets
of this pathway.
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down: a complementary strategy for evaluating an anti-infective target.
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The results described here have thus unraveled the importance
of understanding the vulnerability of a novel target either through
the use of conditional-expression strains and/or via inhibitors
with diverse mechanistic activities before embarking on a drug
discovery program.
ACKNOWLEDGMENTS
We acknowledge the guidance and support provided by Tanjore Balga-
nesh and Santanu Datta for this study. Our sincere thanks to Debasmita
Sarkar for protein supply, Jateendranath Sandesh for analytical support,
and Suresh Solapure and Sunita DeSousa and Janani Venkatraman for
critical input.
We acknowledge support from the Foundation for Strategic Research,
the Swedish Research Council, and Uppsala University.
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