Arcopilins:\nA New\nFamily of Staphylococcus\naureus Biofilm Disruptors from the Soil Fungus Arcopilus navicularis

Biofilms represent\na key challenge in the treatment of microbial\ninfections; for instance, Staphylococcus aureus causes chronic or fatal infections by forming biofilms on medical\ndevices. Herein, the fungus Arcopilus navicularis was found to produce a novel family of PKS-NRPS metabolites that\nare able to disrupt preformed biofilms of S. aureus. Arcopilins A–F (<b>1</b>–<b>6</b>), tetramic\nacids, and arcopilin G (<b>7</b>), a 2-pyridone, were elucidated\nusing HR-ESI-MS and one-dimensional (1D) and two-dimensional (2D)\nnuclear magnetic resonance (NMR) spectroscopy. Their absolute configuration\nwas established by the synthesis of MPTA-esters for <b>2</b>, analysis of <sup>1</sup>H–<sup>1</sup>H coupling constants,\nand ROESY correlations, along with comparison with the crystal structure\nof <b>7</b>. Arcopilin A (<b>1</b>) not only effectively\ndisrupts preformed biofilms of S. aureus but also potentiates the activity of gentamicin and vancomycin up\nto 115- and 31-fold times, respectively. Our findings demonstrate\nthe potential application of arcopilins for the conjugated treatment\nof infections caused by S. aureus with\nantibiotics unable to disrupt preformed biofilms.