An Optimized\nMarinopyrrole A Derivative Targets 6‑Phosphoglucosamine\nSynthetase to Inhibit Methicillin-Resistant <i>Staphylococcus\naureus</i>

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)\nis a common pathogenic bacterium that causes clinical infection and\nhas become one of the most prominent antibiotic-resistant bacteria\nin the world. There is a pressing need to develop new antibiotics\nbased on novel modes of action to combat increasingly severe MRSA\ninfection. Marinopyrrole A (MA), a natural product extracted from\nmarine <i>Streptomyces</i> in 2008, has a unique bipyrrole\nchemical skeleton and shows potent antibacterial activity against\nMRSA. However, its mode of action is still elusive. Herein, we developed\nan optimized MA derivative, MA-D1, and applied a chemoproteomic approach\nto reveal that MA-D1 performs its anti-MRSA activity by directly targeting\n6-phosphoglucosamine synthetase (GlmS) to cause the breakdown of bacterial\ncell wall biosynthesis. Computational and experimental studies showed\nthat MA-D1 interacts with the key R381 and E382 residues of GlmS in\na novel binding pocket. Furthermore, MA-D1 showed a low resistance\nfrequency for MRSA treatment and was also sensitive against the linezolid-,\nvancomycin-, or teicoplanin-resistant MRSA strains. MA-D1 also showed <i>in vivo</i> antibiotic efficacy in multiple animal models. This\nstudy demonstrates the promising potential of targeting GlmS to develop\na new class of antibiotics to control MRSA pathogen infection.