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 16d inhibited protein synthesis and displayed potent activity
against linezolid-resistant Enterococcus faecalis. Although 16d showed cross-resistance to linezolid-resistant
MRSA, the frequency of resistance development of MRSA against 16d was lower compared to that of linezolid. Additionally, 16d exhibited excellent pharmacokinetic properties and superior in vivo efficacy compared to linezolid. Furthermore, compound 16d 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 16d exhibited some similarities with linezolid in its effects
while also demonstrating a distinct mechanism characterized by cell
membrane damage. Moreover, 16d significantly disrupted
the MRSA biofilms. The antibacterial agent 16d represents
a promising candidate for the treatment of serious infections caused
by drug-resistant bacteria.