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
| Autor: | Astha Nautiyal, Kalappa Muniyappa, K. Neelakanteshwar Patil |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Microbiology (medical)
DNA repair Suramin Antitubercular Agents Repressor Microbial Sensitivity Tests Biology Biochemistry Inhibitory Concentration 50 SOS Response (Genetics) chemistry.chemical_compound Drug Discovery medicine Humans Protease Inhibitors Pharmacology (medical) SOS response SOS Response Genetics Adenosine Triphosphatases Pharmacology DNA synthesis Mycobacterium tuberculosis biochemical phenomena metabolism and nutrition Molecular biology Cell biology Rec A Recombinases Infectious Diseases chemistry bacteria Repressor lexA DNA medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 69:1834-1843 |
| ISSN: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dku080 |
| Popis: | 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. 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. 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. 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. |
| Databáze: | OpenAIRE |
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