title: Naphthalimides Selectively Inhibit the Activity of Bacterial, Replicative DNA Ligases and Display Bactericidal Effects against Tubercle Bacilli.
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 theirMycobacterium tuberculosisNAD⁺ 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 ofM. tuberculosisNAD⁺-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.
authors.affiliation: Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. mkorycka@cbm.pan.pl.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Korycka-Machala
authors.affiliation: Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. nowosielskimarcin@gmail.com.|Quantum Chemistry Group, A. Mickiewicz University, Poznan 60-780, Poland. nowosielskimarcin@gmail.com.
authors.forename: Marcin
authors.initials: M
authors.lastname: Nowosielski
authors.affiliation: Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. kanetka1@tlen.pl.
authors.forename: Aneta
authors.initials: A
authors.lastname: Kuron
authors.affiliation: Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. srykowski@cbm.pan.pl.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rykowski
authors.affiliation: Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. aolejniczak@cbm.pan.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Olejniczak
authors.affiliation: Quantum Chemistry Group, A. Mickiewicz University, Poznan 60-780, Poland. mmh@amu.edu.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland. jdziadek@cbm.pan.pl.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dziadek
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D011088:DNA Ligases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D007546:Isoquinolines / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009243:NAD; D053644:Naphthalimides / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D053644:Naphthalimides; C019215:mitonafide; D009243:NAD; C019222:pinafide; D011088:DNA Ligases
keywords: DNA ligase A; Mycobacterium tuberculosis; antituberculosis drugs; naphthalimides