ORCID Profile
0000-0002-0100-4877
Current Organisation
Faculty of natural Sciences Comenius University in Bratislava
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Publisher: American Chemical Society (ACS)
Date: 11-05-2017
DOI: 10.1021/ACSINFECDIS.7B00006
Abstract: Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds. To this purpose the publically available GlaxoSmithKline antimycobacterial compound set was assayed, uncovering a series of 4-(pyridin-2-yl)thiazole derivatives which efficiently inhibit the Mycobacterium tuberculosis PyrG enzyme activity, one of them showing low activity against the human CTP synthetase. The three best compounds were ATP binding site competitive inhibitors, with K
Publisher: Wiley
Date: 29-10-2016
DOI: 10.1111/MMI.13535
Abstract: There is an urgent need to discover new anti-tubercular agents with novel mechanisms of action in order to tackle the scourge of drug-resistant tuberculosis. Here, we report the identification of such a molecule - an AminoPYrimidine-Sulfonamide (APYS1) that has potent, bactericidal activity against M. tuberculosis. Mutations in APYS1-resistant M. tuberculosis mapped exclusively to wag31, a gene that encodes a scaffolding protein thought to orchestrate cell elongation. Recombineering confirmed that a Gln201Arg mutation in Wag31 was sufficient to cause resistance to APYS1, however, neither overexpression nor conditional depletion of wag31 impacted M. tuberculosis susceptibility to this compound. In contrast, expression of the wildtype allele of wag31 in APYS1-resistant M. tuberculosis was dominant and restored susceptibility to APYS1 to wildtype levels. Time-lapse imaging and scanning electron microscopy revealed that APYS1 caused gross malformation of the old pole of M. tuberculosis, with eventual lysis. These effects resembled the morphological changes observed following transcriptional silencing of wag31 in M. tuberculosis. These data show that Wag31 is likely not the direct target of APYS1, but the striking phenotypic similarity between APYS1 exposure and genetic depletion of Wag31 in M. tuberculosis suggests that APYS1 might indirectly affect Wag31 through an as yet unknown mechanism.
Publisher: American Chemical Society (ACS)
Date: 06-01-2016
Publisher: Proceedings of the National Academy of Sciences
Date: 17-06-2013
Abstract: The global problem of TB has worsened in recent years with the emergence of drug-resistant organisms, and new drugs are clearly needed. In a cell-based high-throughput screen, a small molecule, TCA1, was discovered that has activity against replicating and nonreplicating Mycobacterium tuberculosis . It is also efficacious in acute and chronic rodent models of TB alone or combined with frontline TB drugs. TCA1 functions by a unique mechanism, inhibiting enzymes involved in cell wall and molybdenum cofactor biosynthesis. This discovery represents a significant advance in the search for new agents to treat persistent and drug-resistant TB.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2018
DOI: 10.1038/S41598-018-21614-4
Abstract: Mycobacterium tuberculosis , the etiological agent of the infectious disease tuberculosis, kills approximately 1.5 million people annually, while the spread of multidrug-resistant strains is of great global concern. Thus, continuous efforts to identify new antitubercular drugs as well as novel targets are crucial. Recently, two prodrugs activated by the monooxygenase EthA, 7947882 and 7904688, which target the CTP synthetase PyrG, were identified and characterized. In this work, microbiological, biochemical, and in silico methodologies were used to demonstrate that both prodrugs possess a second target, the pantothenate kinase PanK. This enzyme is involved in coenzyme A biosynthesis, an essential pathway for M. tuberculosis growth. Moreover, compound 11426026, the active metabolite of 7947882, was demonstrated to directly inhibit PanK, as well. In an independent screen of a compound library against PyrG, two additional inhibitors were also found to be active against PanK. In conclusion, these direct PyrG and PanK inhibitors can be considered as leads for multitarget antitubercular drugs and these two enzymes could be employed as a “double-tool” in order to find additional hit compounds.
Publisher: American Chemical Society (ACS)
Date: 15-11-2019
DOI: 10.1021/ACSINFECDIS.9B00388
Abstract: The thienopyrimidine TP053 is an antitubercular prodrug active against both replicating and nonreplicating
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.TUBE.2018.08.004
Abstract: The search for compounds with biological activity for many diseases is turning increasingly to drug repurposing. In this study, we have focused on the European Union-approved antimalarial pyronaridine which was found to have in vitro activity against Mycobacterium tuberculosis (MIC 5 μg/mL). In macromolecular synthesis assays, pyronaridine resulted in a severe decrease in incorporation of
Location: Slovakia
No related grants have been discovered for Katarina Mikusova.