Naphthalimides selectively inhibit the activity of bacterial, replicative DNA ligases and display bactericidal effects against tubercle bacilli

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Abstract

The DNA ligases, enzymes that seal breaks in the backbones of DNA, are essential for all organisms, however bacterial ligases essential for DNA replication use β-nicotinamide adenine dinucleotide as their co-factor, whereas those that are essential in eukaryotes and viruses use adenosine-5′-triphosphate. This fact leads to the conclusion that NAD+-dependent DNA ligases in bacteria could be targeted by their co-factor specific inhibitors. The development of novel alternative medical strategies, including new drugs, are a top priority focus areas for tuberculosis research due to an increase in the number of multi-drug resistant as well as totally drug resistant tubercle bacilli strains. Here, through the use of a virtual high-throughput screen and manual inspection of the top 200 records, 23 compounds were selected for in vitro studies. The selected compounds were evaluated in respect to their Mycobacterium tuberculosis NAD+ DNA ligase inhibitory effect by a newly developed assay based on Genetic Analyzer 3500 Sequencer. The most effective agents (e.g., pinafide, mitonafide) inhibited the activity of M. tuberculosis NAD+-dependent DNA ligase A at concentrations of 50 μM. At the same time, the ATP-dependent (phage) DNA LigT4 was unaffected by the agents at concentrations up to 2 mM. The selected compounds appeared to also be active against actively growing tubercle bacilli in concentrations as low as 15 μM.

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Korycka-Machala, M., Nowosielski, M., Kuron, A., Rykowski, S., Olejniczak, A., Hoffmann, M., & Dziadek, J. (2017). Naphthalimides selectively inhibit the activity of bacterial, replicative DNA ligases and display bactericidal effects against tubercle bacilli. Molecules, 22(1). https://doi.org/10.3390/molecules22010154

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