In silico design synthesis and biological evaluation of novel fluoroquinolone analogs with improved potency against fluoroquinolone resistant escherichia coli for the treatment of urinary tract infections

Abstract

Fluoroquinolones (FQs) belong to the class of quinolone drugs that are used to treat Urinary tract infections (UTIs) through inhibition of E. coli DNA gyrase. Resistance to FQs poses a serious problem in the treatment against resistant strains of E. coli which is associated with Ser83 to Leu and Asp87 to Asn mutations at quinolone resistance determining region (QRDR) of GyrA subunit of DNA gyrase. Mutant DNA GyrA (mtDNA GyrA) is deemed to be a significant target for the development of novel FQ drugs. Due to resistance to FQ drugs, discovery or development of novel FQs is crucial to inhibit the mtDNA GyrA. Hence, 3D mtDNA GyrA protein was developed by homology modeling, followed by which, 204 novel FQ analogs were designed. The designed ligands were then screened using molecular docking studies, subjected to structure and ligand-based pharmacophore study followed by ADMET and toxicity (TOPKAT) and 3D-QSAR modeling study. Finally, ten (FQ-49, FQ-70, FQ-131, FQ-132, FQ-137, FQ-147, FQ-151, FQ-172, FQ-177 and FQ-182) hit FQ analogs were shortlisted and synthesized using microwave-assisted technique. The sequence analysis of quinolone- resistance determining region (QRDR) of purified mutant DNA gyrase enzyme confirmed the presence of Ser83Leu and Asp87Asn mutations in the FQ- resistant E. coli isolates from UTI patients. All the synthesised compounds possessed excellent activity against tested FQ-resistant E. coli and inhibited mutant DNA gyrase activity in vitro. Overall, this study confirmed that the synthesized novel FQ-49, FQ-70, FQ-131, FQ-132, FQ-137, FQ-147, FQ-151, m FQ-172, FQ-177 and FQ-182 analogs exhibited extremely potent antibacterial activity against the existing FQ-resistant E. coli which can be further successfully utilized for the treatment of UTIs newline