ml9b00015_si_001.pdf (13.5 MB)
Expanded Structure–Activity Studies of Lipoxazolidinone Antibiotics
journal contribution
posted on 2019-02-28, 18:19 authored by Kaylib
R. Robinson, Jonathan J. Mills, Joshua G. PierceThe
lipoxazolidinone family of marine natural products, which contains
an unusual 4-oxazolidinone core, was found to possess potent antimicrobial
activity against methicillin resistant Staphylococcus aureus (MRSA). Herein, we expanded our previous synthetic efforts by preparing
selected aryl derivatives of the lipoxazolidinones and further evaluating
the potential to expand the activity of this class of molecules to
Gram-negative pathogens. With these analogs, we explored the effect
of varying the substitution pattern around the aromatic ring, increasing
the chain length between the oxazolidinone core and the aryl system,
and how altering the position of more polar functional groups affected
the antimicrobial activity. Finally, we utilized a TolC knockout strain
of E. coli to demonstrate that our compounds are
subject to efflux in Gram-negative pathogens, and activity is restored
in these knockouts. Together these results provide additional data
for the further development of 4-oxazolidinone analogs 5, 20, and 21 for the treatment of infectious
disease.