ja508632y_si_005.cif (200.79 kB)
Axinellamines as Broad-Spectrum Antibacterial Agents: Scalable Synthesis and Biology
dataset
posted on 2015-12-17, 05:30 authored by Rodrigo
A. Rodriguez, Danielle Barrios Steed, Yu Kawamata, Shun Su, Peter A. Smith, Tyler C. Steed, Floyd E. Romesberg, Phil S. BaranAntibiotic-resistant
bacteria present an ongoing challenge to both
chemists and biologists as they seek novel compounds and modes of
action to out-maneuver continually evolving resistance pathways, especially
against Gram-negative strains. The dimeric pyrrole–imidazole
alkaloids represent a unique marine natural product class with diverse
primary biological activity and chemical architecture. This full account
traces the strategy used to develop a second-generation route to key
spirocycle 9, culminating in a practical synthesis of
the axinellamines and enabling their discovery as broad-spectrum
antibacterial agents, with promising activity against both Gram-positive
and Gram-negative bacteria. While their detailed mode of antibacterial
action remains unclear, the axinellamines appear to cause secondary
membrane destabilization and impart an aberrant cellular morphology
consistent with the inhibition of normal septum formation. This study
serves as a rare example of a natural product initially reported to
be devoid of biological activity surfacing as an active antibacterial
agent with an intriguing mode of action.