title: Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Rodriguez
authors.forename: Danielle
authors.initials: D
authors.lastname: Barrios Steed
authors.forename: Yu
authors.initials: Y
authors.lastname: Kawamata
authors.forename: Shun
authors.initials: S
authors.lastname: Su
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smith
authors.forename: Tyler C
authors.initials: TC
authors.lastname: Steed
authors.forename: Floyd E
authors.initials: FE
authors.lastname: Romesberg
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003500:Cyclization; D019791:Guanidine / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010087:Oxides / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D007093:Imidazoles; D010087:Oxides; D011758:Pyrroles; D013141:Spiro Compounds; C520388:axinellamine; D019791:Guanidine