barw Judi Clinical Journal 3105-4102 2 1 2026 06 17 Rational Drug Design Targeting Multidrug-Resistant Microorganisms: A Narrative Review 20 33 10.70955/JCJ.2026.04 eng Khanda A. Anwar Department of Basic Medical Sciences, College of Medicine, University of Sulaimani, Madam Mitterrand Street, Sulaymaniyah, Iraq Fattah H. Fattah Department of Community Medicine, College of Medicine, University of Sulaimani, Madam Mitterrand Street, Sulaymaniyah, Iraq Karokh F. Hama Hussein Department of Gastroenterology, Gastroenterology and Hepatology Teaching Hospital, Zanko Street, Sulaymaniyah, Iraq Ahmed G. Hamasaeed Faculty of Medical Sciences, School of Pharmacy, University of Sulaimani, Madam Mitterrand Street, Sulaymaniyah, Iraq Rebar A. Mohammed Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq Sabah J. Hasan Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq Abdullah D. Ahmed Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq Karokh K. Mohammed Kscien Organization for Scientific Research (Middle East Office), Hamdi Street, Sulaymaniyah, Iraq Shvan L. Ezzat Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq Shvan H. Mohammed Kscien Organization for Scientific Research (Middle East Office), Hamdi Street, Sulaymaniyah, Iraq Suhaib H. Kakamad Research Center, Qaiwan International University, Sulaymaniyah, Kurdistan Region, Iraq Mohammed Q. Mustafa Doctoral School of Health Sciences, Faculty of Health Sciences, University of Pécs, Pécs, Hungary Danyar O. Azeez Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq Hiwa O. Abdullah Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq Fahmi H. Kakamad Department of Scientific Affairs, Smart Health Tower, Madam Mitterrand Street, Sulaymaniyah, Iraq 0000-0002-2124-9580 2026 05 11 Antimicrobial resistance remains a major global health challenge and continues to erode the clinical utility of many existing antibiotics. This review outlines recent advances in rational antibacterial discovery, with emphasis on fully synthetic, structure-guided scaffolds designed to target essential bacterial processes such as cell division, lipid A biosynthesis, DNA replication, and protein synthesis. While many candidate molecules show strong enzymatic inhibition and promising antibacterial activity in vitro, their progress is often limited by poor Gram-negative permeability, active efflux, a narrow spectrum, and off-target toxicity. Recent efforts are therefore focusing on scaffold optimization, prodrug and conjugation strategies, dual-target agents, and combination regimens to improve delivery, broaden activity, and reduce resistance emergence. In parallel, early evaluation of whole-cell potency, efflux liability, pharmacokinetics, and safety appears increasingly important for identifying viable leads. Overall, the evidence suggests that future success in antibacterial development will likely depend on integrating target potency with physicochemical and pharmacological properties from the earliest stages of design.