Design, Synthesis, Molecular Modeling, Biological Activity, and Mechanism of Action of Novel Amino Acid Derivatives of Norfloxacin
Artikel i vetenskaplig tidskrift, 2023

Two series of N4-substituted piperazinyl amino acid derivatives of norfloxacin (24 new compounds) were designed and synthesized to attain structural surrogates with additional binding sites and enhanced antibacterial activity. Synthesized derivatives showed increased antibacterial and antimycobacterial activity compared to their lead structure, norfloxacin. Molecular modeling studies supported the notion that the derivatives can establish additional bonds with the target enzymes gyrase and topoisomerase IV. In vitro enzyme inhibition assays confirmed that the tested compounds were significant inhibitors of these enzymes. Inhibition of gyrase and topoisomerase IV was then confirmed in living bacterial cells using bacterial cytological profiling of both Gram-negative Escherichia coli and Gram-positive Bacillus subtilis, revealing a typical topoisomerase inhibition phenotype characterized by severe nucleoid packing defects. Several derivatives exhibited additional effects on the Gram-positive cell wall synthesis machinery and/or the cytoplasmic membrane, which likely contributed to their increased antibacterial activity. While we could not identify specific cell wall or membrane targets, membrane depolarization was not observed. Our experiments further suggest that cell wall synthesis inhibition most likely occurs outside the membrane-bound lipid II cycle.

Författare

Ahmed M. Kamal El-sagheir

Assiut University

Ireny Abdelmesseh Nekhala Abdelmesseh

Chalmers, Life sciences, Kemisk biologi

Mohammed K. Abd El-Gaber

Assiut University

Ahmed S. Aboraia

Assiut University

Jonatan Persson

Center for Antibiotic Resistance Research

Ann-Britt Schäfer

Chalmers, Life sciences, Kemisk biologi

Michaela Wenzel

Chalmers, Life sciences, Kemisk biologi

Farghaly A. Omar

Assiut University

ACS Omega

24701343 (eISSN)

Vol. 8 45 43271-43284

Ämneskategorier

Biokemi och molekylärbiologi

DOI

10.1021/acsomega.3c07221

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Senast uppdaterat

2024-01-25