Inhibition of the transcriptional repressor LexA: Withstanding drug resistance by inhibiting the bacterial mechanisms of adaptation to antimicrobials

Autor: Donatella Tondi, Giuseppe Celenza, Laura Cendron, Nicola Franceschini, Letizia Di Pietro, Francesca Spyrakis, Mariagrazia Perilli, Francesco De Angelis, Samantha Reale, Pierangelo Bellio, Alisia Mancini, Gianfranco Amicosante, Salvatore Cracchiolo
Rok vydání: 2020
Předmět:
Boron Compounds
0301 basic medicine
In silico
Drug Resistance
RecA protein
Levofloxacin
Microbial Sensitivity Tests
030226 pharmacology & pharmacy
General Biochemistry
Genetics and Molecular Biology
LexA inhibition
03 medical and health sciences
0302 clinical medicine
Bacterial Proteins
Filamentation
Drug Resistance
Bacterial
Genetics
Escherichia coli
General Pharmacology
Toxicology and Pharmaceutics
SOS response
SOS Response
Genetics
Gene
SOS Response
chemistry.chemical_classification
Bacterial SOS response
Covalent inhibition
Phenylboronic acid derivatives
Anti-Bacterial Agents
Molecular Docking Simulation
Serine Endopeptidases
biology
Bacterial
Active site
General Medicine
biochemical phenomena
metabolism
and nutrition
biology.organism_classification
Cell biology
enzymes and coenzymes (carbohydrates)
030104 developmental biology
Enzyme
chemistry
biology.protein
bacteria
Repressor lexA
Bacteria
Zdroj: Life Sciences. 241:117116
ISSN: 0024-3205
DOI: 10.1016/j.lfs.2019.117116
Popis: Aims LexA protein is a transcriptional repressor which regulates the expression of more than 60 genes belonging to the SOS global regulatory network activated by damages to bacterial DNA. Considering its role in bacteria, LexA represents a key target to counteract bacterial resistance: the possibility to modulate SOS response through the inhibition of LexA autoproteolysis may lead to reduced drug susceptibility and acquisition of resistance in bacteria. In our study we investigated boron-containing compounds as potential inhibitors of LexA self-cleavage. Main methods The inhibition of LexA self-cleavage was evaluated by following the variation of the first-order rate constant by LC-MS at several concentrations of inhibitors. In silico analysis was applied to predict the binding orientations assumed by the inhibitors in the protein active site, upon covalent binding to the catalytic Ser-119. Bacterial filamentation assay was used to confirm the ability of (3-aminophenyl)boronic acid to interfere with SOS induced activation. Key findings Boron-containing compounds act as inhibitors of LexA self-cleavage, as also confirmed by molecular modelling where the compounds interact with the catalytic Ser-119, via the formation of an acyl-enzyme intermediate. A new equation for the description of the inhibition potency in an autoproteolytic enzyme is also disclosed. Bacterial filamentation assays strongly support the interference of our compounds with the SOS response activation through inhibition of septum formation. Significance The obtained results demonstrated that phenylboronic compounds could be exploited in a hit-to-lead optimization process toward effective LexA self-cleavage inhibitors. They would sustain the rehabilitation in therapy of several dismissed antibiotics.
Databáze: OpenAIRE
Externí odkaz: