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Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology.

Rodriguez RA, Barrios Steed D, Kawamata Y, Su S, Smith PA, Steed TC, Romesberg FE, Baran PS - J. Am. Chem. Soc. (2014)

Bottom Line: The dimeric pyrrole-imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
Antibiotic-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.

Show MeSH
TfNH2 Effecton Model ChlorospirocyclizationAddition of 1.0 equiv of TfNH2 to 53 produced 55 in quantitativeyield.
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sch5: TfNH2 Effecton Model ChlorospirocyclizationAddition of 1.0 equiv of TfNH2 to 53 produced 55 in quantitativeyield.


Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology.

Rodriguez RA, Barrios Steed D, Kawamata Y, Su S, Smith PA, Steed TC, Romesberg FE, Baran PS - J. Am. Chem. Soc. (2014)

TfNH2 Effecton Model ChlorospirocyclizationAddition of 1.0 equiv of TfNH2 to 53 produced 55 in quantitativeyield.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4227811&req=5

sch5: TfNH2 Effecton Model ChlorospirocyclizationAddition of 1.0 equiv of TfNH2 to 53 produced 55 in quantitativeyield.
Bottom Line: The dimeric pyrrole-imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
Antibiotic-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.

Show MeSH