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Naphthalimides Selectively Inhibit the Activity of Bacterial, Replicative DNA Ligases and Display Bactericidal Effects against Tubercle Bacilli.
Korycka-Machala, Malgorzata; Nowosielski, Marcin; Kuron, Aneta; Rykowski, Sebastian; Olejniczak, Agnieszka; Hoffmann, Marcin; Dziadek, Jaroslaw.
Afiliação
  • Korycka-Machala M; Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. mkorycka@cbm.pan.pl.
  • Nowosielski M; Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. nowosielskimarcin@gmail.com.
  • Kuron A; Quantum Chemistry Group, A. Mickiewicz University, Poznan 60-780, Poland. nowosielskimarcin@gmail.com.
  • Rykowski S; Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. kanetka1@tlen.pl.
  • Olejniczak A; Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. srykowski@cbm.pan.pl.
  • Hoffmann M; Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. aolejniczak@cbm.pan.pl.
  • Dziadek J; Quantum Chemistry Group, A. Mickiewicz University, Poznan 60-780, Poland. mmh@amu.edu.pl.
Molecules ; 22(1)2017 Jan 17.
Article em En | MEDLINE | ID: mdl-28106753
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 ß-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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA Ligases / Naftalimidas / Mycobacterium tuberculosis / Antituberculosos Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA Ligases / Naftalimidas / Mycobacterium tuberculosis / Antituberculosos Idioma: En Ano de publicação: 2017 Tipo de documento: Article