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

Abstract

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.

Efficient Synthesis of 2-Aminopyridine Derivatives: Antibacterial Activity Assessment and Molecular Docking Studies

“…Two strong conventional H-bonds [ 18 , 19 ] were observed: the first one was observed between the hydrogen atom of the compound and active site residues GLU(A:58) with a bond distance of 2.62 Å, and the secondwas established between the oxygen atom of the compound and the active site residues THR(A:173) with a bond distance of 2.88 Å. We can clearly see these two residues: GLU(A:58) and THR(A:173), play an important role in the active site of S. aureus (PDB ID: 4URM), which have been reported inprevious studies [ 20 , 21 ].…”

Design, Synthesis, Antibacterial Evaluations and In Silico Studies of Novel Thiosemicarbazides and 1,3,4-Thiadiazoles

“…The research work carried out by our team in previous years indicates the high potential of aryl thiosemicarbazides to inhibit type IIA topoisomerases (DNA gyrase and topoisomerase IV) [ 26 , 27 , 28 , 29 ]. This activity interferes with bacterial DNA synthesis, ultimately resulting in inhibition of their replication.…”

New Indole‐6‐Carboxylic Acid Derivatives as Multi‐Target Antiproliferative Agents: Synthesis, in Silico Studies, and Cytotoxicity Evaluation

“…Industrially significant applications, such as anti-corrosion and anti-fouling properties, have been attributed to their derivatives as well. [8] Therefore, they occupy a vital place in pharmaceutical synthesis as anticancer, [9] antibacterial, [10] anti-HIV, [11] and antioxidant. [12] Oxadiazole is a small five membered heterocycle with a flat surface that is effective in target binding by pi-stacking interaction, making it essential in drug design.…”

“…Industrially significant applications, such as anti‐corrosion and anti‐fouling properties, have been attributed to their derivatives as well [8] . Therefore, they occupy a vital place in pharmaceutical synthesis as anticancer, [9] antibacterial, [10] anti‐HIV, [11] and antioxidant [12] …”