Tricyclic Benzo[1,3]oxazinyloxazolidinones\nas Potent\nAntibacterial Agents against Drug-Resistant Pathogens

Herein, we developed a series of benzo[1,3]oxazinyloxazolidinones\nas potent antibacterial agents. Some of the compounds exhibited potent\nantibacterial activity against a range of clinical drug-resistant\npathogens, including Mtb, MRSA, MRSE, VISA, and VRE. Notably, compound <b>16d</b> inhibited protein synthesis and displayed potent activity\nagainst linezolid-resistant Enterococcus faecalis. Although <b>16d</b> showed cross-resistance to linezolid-resistant\nMRSA, 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\nchanges in major organs of bacterially infected mice. Hoechst-PI double\nstaining and scanning electron microscopy analyses revealed that <b>16d</b> exhibited some similarities with linezolid in its effects\nwhile also demonstrating a distinct mechanism characterized by cell\nmembrane damage. Moreover, <b>16d</b> significantly disrupted\nthe MRSA biofilms. The antibacterial agent <b>16d</b> represents\na promising candidate for the treatment of serious infections caused\nby drug-resistant bacteria.