Next Article in Journal
JNK Pathway in CNS Pathologies
Previous Article in Journal
Tissue-Specific Accumulation and Isomerization of Valuable Phenylethanoid Glycosides from Plantago and Forsythia Plants
Article

Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis

1
Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12/16, 90-237 Łódź, Poland
2
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
3
Department of Molecular Microbiology, Faculty of Biotechnology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland
4
Institute of Applied Radiation Chemistry, Łódź University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
5
International Centre for Research on Innovative Biobased Materials (ICRI-BioM)—International Research Agenda, Łódź University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(8), 3881; https://doi.org/10.3390/ijms22083881
Received: 8 March 2021 / Revised: 1 April 2021 / Accepted: 6 April 2021 / Published: 9 April 2021
(This article belongs to the Section Biochemistry)
Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases. View Full-Text
Keywords: thiosemicarbazides; antibacterial agents; molecular modelling; bacterial type IIA topoisomerases; DNA replication; time-lapse microfluidic microscopy thiosemicarbazides; antibacterial agents; molecular modelling; bacterial type IIA topoisomerases; DNA replication; time-lapse microfluidic microscopy
Show Figures

Figure 1

MDPI and ACS Style

Kowalczyk, A.; Paneth, A.; Trojanowski, D.; Paneth, P.; Zakrzewska-Czerwińska, J.; Stączek, P. Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis. Int. J. Mol. Sci. 2021, 22, 3881. https://doi.org/10.3390/ijms22083881

AMA Style

Kowalczyk A, Paneth A, Trojanowski D, Paneth P, Zakrzewska-Czerwińska J, Stączek P. Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis. International Journal of Molecular Sciences. 2021; 22(8):3881. https://doi.org/10.3390/ijms22083881

Chicago/Turabian Style

Kowalczyk, Aleksandra, Agata Paneth, Damian Trojanowski, Piotr Paneth, Jolanta Zakrzewska-Czerwińska, and Paweł Stączek. 2021. "Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis" International Journal of Molecular Sciences 22, no. 8: 3881. https://doi.org/10.3390/ijms22083881

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop