The emergence of multidrug-resistant Gram-positive bacterial pathogens is a problem of ever increasing significance, with organisms like methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant streptococci challenging therapy. Vancomycin, a last resort drug, now faces staphylococcal strains with reduced susceptibility. Oxazolidinones are synthetic antibacterial agents with potent activity against Gram-positive organisms, acting by selectively binding to the 50S ribosomal subunit to inhibit protein synthesis initiation, with no cross-resistance to other antibiotics. To increase Gram-positive activity and expand the spectrum to fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis, an extensive structure-activity relationship (SAR) study replaced the morpholine moiety of linezolid with aromatic five-membered nitrogen-containing heterocycles (azoles). (Pyrrolylphenyl)- and (pyrazolylphenyl) oxazolidinones were discovered, with 3-cyanopyrrole and 4-cyanopyrazole moieties imparting excellent broad-spectrum activity. PNU-171933 and PNU-172576 demonstrated potent in vitro antibacterial activity: MICs <0.125-0.5 µg/mL against Gram-positive bacteria (including MRSA, VRE) and 2-4 µg/mL against H. influenzae and M. catarrhalis. In vivo, they were effective against lethal systemic S. aureus and S. pneumoniae infections in mice, with PNU-172576 more potent than linezolid against S. pneumoniae. Both compounds had excellent pharmacokinetic profiles: absolute oral bioavailability of 92% (PNU-171933) and 80% (PNU-172576), harmonic mean apparent terminal disposition half-lives >5 h, high blood levels, moderate volume of distribution, and low clearance. These are the first oxazolidinones reported to have potent activity against both Gram-positive and Gram-negative bacteria.