The emergence of multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP) poses a severe threat to public health, with limited effective therapies available. To address this challenge, researchers at the Upjohn Company (a legacy of Pfizer) built on early work by DuPont on oxazolidinone compounds and conducted extensive structure-activity relationship (SAR) studies, optimized toxicity profiles through early preclinical animal safety evaluations, and developed efficient synthetic methods (including the Manninen reaction for enantioselective synthesis). Through these efforts, the team identified two clinical candidates, eperezolid and linezolid. Linezolid (ZYVOX), the first member of the oxazolidinone class, became the first completely new class of antibiotics approved by the FDA in over 35 years (since nalidixic acid in 1963). It operates via a unique mechanism of inhibiting bacterial protein synthesis, demonstrates potent activity against multidrug-resistant Gram-positive pathogens, and features both intravenous and oral formulations. Approved in 2000, linezolid addresses the critical need for effective therapies against serious Gram-positive infections caused by resistant strains.