Tricyclic Benzo[1,3]oxazinyloxazolidinones as Potent Antibacterial Agents against Drug-Resistant Pathogens

Herein, we developed a series of benzo[1,3]oxazinyloxazolidinones as potent antibacterial agents. Some of the compounds exhibited potent antibacterial activity against a range of clinical drug-resistant pathogens, including Mtb, MRSA, MRSE, VISA, and VRE. Notably, compound <b>16d</b> inhibited protein synthesis and displayed potent activity against linezolid-resistant <i>Enterococcus faecalis</i>. Although <b>16d</b> showed cross-resistance to linezolid-resistant MRSA, the frequency of resistance development of MRSA against <b>16d</b> was lower compared to that of linezolid. Additionally, <b>16d</b> exhibited excellent pharmacokinetic properties and superior <i>in vivo</i> efficacy compared to linezolid. Furthermore, compound <b>16d</b> modulated cytokine levels and ameliorated histopathological changes in major organs of bacterially infected mice. Hoechst-PI double staining and scanning electron microscopy analyses revealed that <b>16d</b> exhibited some similarities with linezolid in its effects while also demonstrating a distinct mechanism characterized by cell membrane damage. Moreover, <b>16d</b> significantly disrupted the MRSA biofilms. The antibacterial agent <b>16d</b> represents a promising candidate for the treatment of serious infections caused by drug-resistant bacteria.