Novel Tetrazole-Based Antimicrobial Agents Targeting Clinical Bacteria Strains: Exploring the Inhibition of Staphylococcus aureus DNA Topoisomerase IV and Gyrase

Abstract

Eleven novel imide-tetrazoles were synthesized. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for antimicrobial activity using standard and clinical strains. Within the studied group, compounds 1–3 were recognized as leading structures with the most promising results in antimicrobial studies. Minimal inhibitory concentration values for compounds 1, 2, 3 were within the range of 0.8–3.2 μg/mL for standard and clinical Gram-positive and Gram-negative bacterial strains, showing in some cases higher activity than the reference Ciprofloxacin. Additionally, all three inhibited the growth of all clinical Staphylococci panels: Staphylococcus aureus (T5592; T5591) and Staphylococcus epidermidis (5253; 4243) with MIC values of 0.8 μg/mL. Selected compounds were examined in topoisomerase IV decatenation assay and DNA gyrase supercoiling assay, followed by suitable molecular docking studies to explore the possible binding modes. In summary, the presented transition from substrate imide-thioureas to imide-tetrazole derivatives resulted in significant increase of antimicrobial properties. The compounds 1–3 proposed here provide a promising basis for further exploration towards novel antimicrobial drug candidates.

Synthesis of tetrazole hybridized with thiazole, thiophene or thiadiazole derivatives, molecular modelling and antimicrobial activity

“…The ATP connecting site on DNA gyrase subunit B is an appealing target for the development of new antibacterial agents. PDB ID: 4URO from the RCSB library was employed to express the crystal configuration of the ATP interacting domain of S. aureus DNA Gyrase subunit B ( Roszkowski et al, 2021 ). In the in-silico investigation of the antibacterial effectiveness of tetrazole hybridized with thiazole, thiophene or thiadiazole derivatives towards S. aureus DNA Gyrase subunit B.…”

Synthesis, Characterization and Studying Biological Activity of Heterocyclic Compounds

“…19 Heterocycles based on tetrazoles are effective antibacterial and anticancer drugs. 20,21 Experimental Without additional purification, commercially available reagents were used. The melting points were calculated using the Stuart SMP 30 equipment and were not adjusted.…”

Design and Synthesis of Menthol and Thymol Derived Ciprofloxacin: Influence of Structural Modifications on the Antibacterial Activity and Anticancer Properties

“…Encouraged by published results related to Ciprofloxacin-monoterpenes hybrids and our experience in research for new antimicrobial agents [ 29 , 30 , 31 , 32 , 33 ], we have decided to design and synthesize series of Ciprofloxacin derivatives with the utilization of menthol and thymol scaffolds. Furthermore, we wanted to explore the impact on antimicrobial activity, cytotoxicity and some of the physicochemical properties of novel compounds versus reference Ciprofloxacin.…”