np9b01174_si_001.pdf (10.72 MB)
Initial Analysis of the Arylomycin D Antibiotics
journal contribution
posted on 2020-07-02, 17:36 authored by Yun Xuan Tan, David S. Peters, Shawn I. Walsh, Matthew Holcomb, Diogo Santos-Martins, Stefano Forli, Floyd E. RomesbergThe arylomycins are a class of natural
product antibiotics that
inhibit bacterial type I signal peptidase and are under development
as therapeutics. Four classes of arylomycins are known, arylomycins
A–D. Previously, we reported the synthesis and analysis of
representatives of the A, B, and C classes and showed that their spectrum
of activity has the potential to be much broader than originally assumed.
Along with a comparison of the mechanism of acquired and innate resistance,
this led us to suggest that the arylomycins are latent antibiotics,
antibiotics that once possessed broad-spectrum activity, but which
upon examination today, have only narrow spectrum activity due to
prior selection for resistance in the course of the competition with
other microorganisms that drove their evolution in the first place.
Interestingly, actinocarbasin, the only identified member of the arylomycin
D class, has been reported to have activity against MRSA. To confirm
and understand this activity, several actinocarbasin derivatives were
synthesized. We demonstrate that the previously reported structure
of actinocarbasin is incorrect, identify what is likely the correct
scaffold, confirm that scaffold has activity against MRSA, and determine
the origin of this activity.