Atromentin B, Obtained by Microbial Fermentation and Total Synthesis, Potentiates the Activity of β‑Lactams Against Methicillin-Resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) poses a major clinical threat due to resistance to β-lactam
antibiotics, such as cefazolin. Although several conventional antibiotics
can be used for the treatment of MRSA, the rapid emergence of resistant
strains limits their utility. To address this challenge, we envisioned
that a combination therapy using β-lactam potentiators would
be a promising approach to expand the application of cefazolin to
MRSA. In this study, with our aim to explore natural products that
potentiate the β-lactams against clinical MRSA strains, we identified
a new atromentin A congener, named atromentin B (1),
from the culture broth of Aspergillus sp. FKI-9941.
Although our structural analysis revealed the presence of a 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione
motif in 1, the inherent 13C NMR propensity
of this class of compounds made definitive structural confirmation
difficult. In addition, its low productivity through fermentation
limited detailed biological evaluation. The total synthesis of 1 enabled unambiguous structural determination and provided
sufficient information for biological studies. The synthetic sample
of 1 exhibited cefazolin potentiation activity comparable
to the naturally occurring product. Combination assays demonstrated
that 1 enhanced cefazolin activity, even against clinical
MRSA isolates. These findings show that atromentin B (1) is a promising β-lactam potentiator.