Brillouin zone folding enabled broadband quasi-bound states in the continuum in lattice-perturbed moiré photonic crystal slabs.

INTRODUCTION

Linezolid is an oxazolidinone antibacterial agent that acts by binding to the 23S rRNA of the bacterial 50S ribosomal subunit to inhibit protein synthesis and exhibits potent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Although resistance to linezolid remains relatively low, its clinical use is limited by safety concerns arising from inhibition of monoamine oxidase A (MAO-A). To address this limitation, we designed and synthesized a series of novel oxazolidinone derivatives with reduced MAO-A inhibition and preserved antibacterial potency.

METHODS

We applied a rational drug design strategy based on the distinct binding models of linezolid within human MAO-A and the ribosomal large subunit of Staphylococcus aureus (S. aureus). Molecular docking was used to screen designed compounds for high affinity toward the S. aureus ribosome and low affinity toward MAO-A. Selected compounds were synthesized and evaluated for in vitro antibacterial activity against Gram-positive bacteria. Compounds with strong antibacterial activity were further assessed for MAO-A inhibition, anti-Mycobacterium tuberculosis (M. tuberculosis) activity, and cytotoxicity.

RESULTS & DISCUSSION: This strategy led to the identification of compound 3a as a highly promising oxazolidinone derivative. 3a exhibited superior antibacterial activity compared with linezolid against S. aureus, methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis (S. epidermidis), and Enterococcus faecalis (E. faecalis), with minimum inhibitory concentrations (MIC) of approximately 0.5-1 μg/mL. Importantly, 3a showed significantly reduced inhibitory activity against human MAO-A. The compound also retained potent activity against M. tuberculosis H37Rv and displayed low cytotoxicity toward human cells. Notably, 3a possesses core potential as a lead compound for the development of next-generation of oxazolidinone antibiotics.

CONCLUSION

These results closely validated our rational design strategy.