The rapid rise of antibiotic-resistant bacterial strains is a significant global health issue, necessitating the development of new and effective antimicrobial agents. This study focuses on designing synthetic de novo models of fluoroquinolone (FQ) descriptors by fusing the quinolone ring-a derivative of FQs-with potential ATPase inhibitors, which is identified through pharmacophore modeling targeting the DNA gyrase B (gyrB) protein of S. aureus. Initially, the pharmacophore model was generated based on the DNA gyrB protein (PDB IDs: 3TTZ, 3U2D, and 3U2K), specifically targeting their co-crystalized ATPase inhibitors to develop a shared feature pharmacophore (SFP) with key features including hydrophobic regions, hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), aromatic moieties (Ar), and halogen bond donors (XBD). The map was further evaluated using the goodness-of-hit (GH) score of 0.2641, indicating the map's strength in capturing potential compounds. The SFP was used for virtual screening against 160,000 compounds from ZINCpharmer and ChEMBL, resulting in 74 hits (48 from ZINCpharmer and 26 from ChEMBL) with similar ATPase features and exhibiting the best-fit scores ranging from 73.50 to 76.80 and RMSD values from 0.1 to 0.5. These identified ligands were fused with the quinolone ring of FQs using genetic algorithms and fragment-based design to create 50 new synthetic models of FQs. Most of these models contain Pyrrole rings, average similarity of more than 55 %, and a Synthetic Accessibility Score (SAScore) ≤ 3.5 for practical syntheses in the lab. These conformers were evaluated through pharmacokinetics and molecular docking, revealing three top compounds-Molecule 13 (-9.1 kcal/mol), Molecule 20 (-9.1 kcal/mol), and Molecule 49 (-9.4 kcal/mol)-which showed greater binding affinity with the DNA gyrase protein (PDB ID: 4PLB) compare to control, Ciprofloxacin (-7.8 kcal/mol). Additionally, 200 ns Molecular Dynamics Simulations (MDS) were conducted using the Schrödinger suite for these three compounds and control, where Molecule 13 showed potential structural stability. To ensure practical feasibility, computational sequence-to-sequence retrosynthesis, and chemical scaffold comparison analysis were employed to design synthetic routes for the most promising compounds, confirming their likelihood of successful synthesis in the lab. The findings of this study contribute to the ongoing efforts to treat antibiotic resistance by providing a framework for designing and evaluating new antimicrobial agents with improved efficacy.