Inhibitors of RecA activity discovered by high-throughput screening: cell-permeable small molecules attenuate the SOS response in Escherichia coli.
The phenomenon of antibiotic resistance has created a need for the development of novel antibiotic classes with nonclassical cellular targets. Unfortunately, target-based drug discovery against proteins considered essential for in vitro bacterial viability has yielded few new therapeutic classes of antibiotics. Targeting the large proportion of genes considered nonessential that have yet to be explored by high-throughput screening, for example, RecA, can complement these efforts. Recent evidence suggests that RecA-controlled processes are responsible for tolerance to antibiotic chemotherapy and are involved in pathways that ultimately lead to full-fledged antibiotic resistance. Therefore inhibitors of RecA may serve as therapeutic adjuvants in combination chemotherapy of bacterial infectious diseases. Toward the goal of validating RecA as a novel target in the chemotherapy of bacterial infections, the authors have screened 35,780 small molecules against RecA. In total, 80 small molecules were identified as primary hits and could be clustered in 6 distinct chemotype clades. The most potent class of hits was further examined, and 1 member compound was found to inhibit RecA-mediated strand exchange and prevent ciprofloxacin-induced SOS expression in Escherichia coli. This compound represents the first small molecule demonstrating an ability to inhibit the bacterial SOS response in live bacterial cell cultures.
Wigle
Tim J
TJ
UNC Eshelman School of Pharmacy, Division of Medicinal Chemistry and Natural Products, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA.
Sexton
Jonathan Z
JZ
Gromova
Anna V
AV
Hadimani
Mallinath B
MB
Hughes
Mark A
MA
Smith
Ginger R
GR
Yeh
Li-An
LA
Singleton
Scott F
SF
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000890:Anti-Infective Agents / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002939:Ciprofloxacin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism*; D057166:High-Throughput Screening Assays / Q000379:methods*; D015394:Molecular Structure; D011938:Rec A Recombinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D013014:SOS Response, Genetics / Q000187:drug effects*; D054852:Small Molecule Libraries
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D054852:Small Molecule Libraries; D002939:Ciprofloxacin; D011938:Rec A Recombinases; D000251:Adenosine Triphosphatases
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