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Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery.

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Relation http://ir.cftri.com/14738/
https://dx.doi.org/10.1093/jac/dku080
 
Title Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis
RecA protein and the SOS response: RecA as a potential target
for antibacterial drug discovery.
 
Creator Astha, Nautiyal
Neelakanteshwar Patil, K.
Muniyappa, K.
 
Subject 11 Antibiotics Chemistry
 
Description Objectives: In eubacteria, RecA is essential for recombinational DNA repair and for stalled replication forks to
resume DNA synthesis. Recent work has implicated a role for RecA in the development of antibiotic resistance
in pathogenic bacteria. Consequently, our goal is to identify and characterize small-molecule inhibitors that
target RecA both in vitro and in vivo.
Methods: We employed ATPase, DNA strand exchange and LexA cleavage assays to elucidate the inhibitory
effects of suramin on Mycobacterium tuberculosis RecA. To gain insights into the mechanism of suramin action,
we directly visualized the structure of RecA nucleoprotein filaments by atomic force microscopy. To determine the
specificity of suramin action in vivo, we investigated its effect on the SOS response by pull-down and western blot
assays as well as for its antibacterial activity.
Results: We show that suramin is a potent inhibitor of DNA strand exchange and ATPase activities of bacterial
RecA proteins with IC50 values in the low micromolar range. Additional evidence shows that suramin inhibits
RecA-catalysed proteolytic cleavage of the LexA repressor. The mechanism underlying such inhibitory actions
of suramin involves its ability to disassemble RecA–single-stranded DNA filaments. Notably, suramin abolished
ciprofloxacin-induced recA gene expression and the SOS response and augmented the bactericidal action of
ciprofloxacin.
Conclusions: Our findings suggest a strategy to chemically disrupt the vital processes controlled by RecA and
hence the promise of small molecules for use against drug-susceptible as well as drug-resistant strains of
M. tuberculosis for better infection control and the development of new therapies.
 
Date 2014
 
Type Article
PeerReviewed
 
Format pdf
 
Language en
 
Identifier http://ir.cftri.com/14738/1/J%20Antimicrob%20Chemother%202014%3B%2069%201834%E2%80%931843.pdf
Astha, Nautiyal and Neelakanteshwar Patil, K. and Muniyappa, K. (2014) Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery. Journal of Antimicrobial Chemotherapy, 69. pp. 1834-1843.