Iizuchalasin A: A Marine Fungal Metabolite With a Cage-Like Structure That Binds TarG to Inhibit Wall Teichoic Acid Biosynthesis by Multidrug-Resistant S. aureus.

To address the ongoing Staphylococcus aureus drug resistance, we screened marine fungal extracts against a multidrug-resistant strain and performed a metabolome analysis to identified new antibiotics with larger molecular size. Targeted isolation yielded eight merocytochalasans, including four new compounds (1,4-6), structurally characterized by MS, NMR, and x-ray single-crystal diffraction data analysis. Compound 1 possessing a unique cage-like symmetrical skeleton, effectively suppressed growth, adhesion, and virulence of methicillin-resistant S. aureus (MRSA), demonstrated potent efficacy in reducing bacterial burden in a mouse skin infection model, and exhibited low resistance development potential. Mechanistically, 1 binds the transmembrane component of the ABC transporter TarGH, and inhibiting its ATPase activity.