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Molecules 2017, 22(1), 154; doi:10.3390/molecules22010154

Naphthalimides Selectively Inhibit the Activity of Bacterial, Replicative DNA Ligases and Display Bactericidal Effects against Tubercle Bacilli

1
Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland
2
Quantum Chemistry Group, A. Mickiewicz University, Poznan 60-780, Poland
These authors contributed equally to this paper.
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 3 January 2017 / Revised: 12 January 2017 / Accepted: 14 January 2017 / Published: 17 January 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1196 KB, uploaded 17 January 2017]   |  

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. View Full-Text
Keywords: Mycobacterium tuberculosis; DNA ligase A; naphthalimides; antituberculosis drugs Mycobacterium tuberculosis; DNA ligase A; naphthalimides; antituberculosis drugs
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Korycka-Machala, M.; Nowosielski, M.; Kuron, A.; Rykowski, S.; Olejniczak, A.; Hoffmann, M.; Dziadek, J. Naphthalimides Selectively Inhibit the Activity of Bacterial, Replicative DNA Ligases and Display Bactericidal Effects against Tubercle Bacilli. Molecules 2017, 22, 154.

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