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SOS response in bacteria: Inhibitory activity of lichen secondary metabolites against Escherichia coli RecA protein
- Source :
- Phytomedicine. 29:11-18
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Background RecA is a bacterial multifunctional protein essential to genetic recombination, error-prone replicative bypass of DNA damages and regulation of SOS response. The activation of bacterial SOS response is directly related to the development of intrinsic and/or acquired resistance to antimicrobials. Although recent studies directed towards RecA inactivation via ATP binding inhibition described a variety of micromolar affinity ligands, inhibitors of the DNA binding site are still unknown. Purpose Twenty-seven secondary metabolites classified as anthraquinones, depsides, depsidones, dibenzofurans, diphenyl-butenolides, paraconic acids, pseudo-depsidones, triterpenes and xanthones, were investigated for their ability to inhibit RecA from Escherichia coli. They were isolated in various Chilean regions from 14 families and 19 genera of lichens. Methods The ATP hydrolytic activity of RecA was quantified detecting the generation of free phosphate in solution. The percentage of inhibition was calculated fixing at 100 µM the concentration of the compounds. Deeper investigations were reserved to those compounds showing an inhibition higher than 80%. To clarify the mechanism of inhibition, the semi-log plot of the percentage of inhibition vs. ATP and vs. ssDNA, was evaluated. Results Only nine compounds showed a percentage of RecA inhibition higher than 80% (divaricatic, perlatolic, alpha-collatolic, lobaric, lichesterinic, protolichesterinic, epiphorellic acids, sphaerophorin and tumidulin). The half-inhibitory concentrations (IC50) calculated for these compounds were ranging from 14.2 µM for protolichesterinic acid to 42.6 µM for sphaerophorin. Investigations on the mechanism of inhibition showed that all compounds behaved as uncompetitive inhibitors for ATP binding site, with the exception of epiphorellic acid which clearly acted as non-competitive inhibitor of the ATP site. Further investigations demonstrated that epiphorellic acid competitively binds the ssDNA binding site. Kinetic data were confirmed by molecular modelling binding predictions which shows that epiphorellic acid is expected to bind the ssDNA site into the L2 loop of RecA protein. Conclusion In this paper the first RecA ssDNA binding site ligand is described. Our study sets epiphorellic acid as a promising hit for the development of more effective RecA inhibitors. In our drug discovery approach, natural products in general and lichen in particular, represent a successful source of active ligands and structural diversity.
- Subjects :
- 0301 basic medicine
Bacterial resistance
Lichen secondary metabolite
Natural source inhibitor
RecA
SOS response
Lichens
Drug Evaluation, Preclinical
DNA, Single-Stranded
Secondary Metabolism
Pharmaceutical Science
Biology
medicine.disease_cause
Genetic recombination
03 medical and health sciences
chemistry.chemical_compound
Adenosine Triphosphate
4-Butyrolactone
Drug Discovery
Escherichia coli
medicine
Chile
Binding site
SOS Response, Genetics
IC50
Pharmacology
Binding Sites
Escherichia coli Proteins
Hydrolysis
bacterial resistance
lichen secondary metabolite
natural source inhibitor
molecular medicine
pharmacology
3003
drug discovery3003 pharmaceutical science
complementary and alternative medicine
biology.organism_classification
Anti-Bacterial Agents
DNA binding site
Rec A Recombinases
030104 developmental biology
Complementary and alternative medicine
chemistry
Biochemistry
Molecular Medicine
DNA
Bacteria
Subjects
Details
- ISSN :
- 09447113
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Phytomedicine
- Accession number :
- edsair.doi.dedup.....c035c86ef4d2264dc0193083888e7d26