Arcopilins: A New Family of Staphylococcus aureus Biofilm Disruptors from the Soil Fungus Arcopilus navicularis

  • J Med Chem. 2024 Sep 12;67(17):15029-15040. doi: 10.1021/acs.jmedchem.4c00585.
Esteban Charria-Girón  1  2 ,  Haoxuan Zeng  1  2 ,  Tatiana E Gorelik  3  4 ,  Alexandra Pahl  1 ,  Khai-Nghi Truong  5 ,  Hedda Schrey  1  2 ,  Frank Surup  1  2 ,  Yasmina Marin-Felix  1  2
Affiliations
  • 1. Department Microbial Drugs, Helmholtz Centre for Infection Research (HZI), German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
  • 2. Institute of Microbiology, Technische Universität Braunschweig, Spielmannstraße 7, 38106 Braunschweig, Germany.
  • 3. Department Structure and Function of Proteins, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
  • 4. Department Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, 66123 Saarbrücken, Germany.
  • 5. Rigaku Europe SE, Hugenottenallee 167, 63263 Neu-Isenburg, Germany.
PMID: 39141525 DOI: 10.1021/acs.jmedchem.4c00585
Abstract

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

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