Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus.

Antibiotic resistance is a serious threat to global public health, and methicillin-resistant Staphylococcus aureus (MRSA) is a poignant example. The macrolactone natural product albocycline, derived from various Streptomyces strains, was recently identified as a promising antibiotic candidate for the treatment of both MRSA and vancomycin-resistant S. aureus (VRSA), which is another clinically relevant and antibiotic resistant strain. Moreover, it was hypothesized that albocycline's antimicrobial activity was derived from the inhibition of peptidoglycan (i.e., bacterial cell wall) biosynthesis. Herein, preliminary mechanistic studies are performed to test the hypothesis that albocycline inhibits MurA, the enzyme that catalyzes the first step of peptidoglycan biosynthesis, using a combination of biological assays alongside molecular modeling and simulation studies. Computational modeling suggests albocycline exists as two conformations in solution, and computational docking of these conformations to an ensemble of simulated receptor structures correctly predicted preferential binding to S. aureus MurA-the enzyme that catalyzes the first step of peptidoglycan biosynthesis-over Escherichia coli (E. coli) MurA. Albocycline isolated from the producing organism (Streptomyces maizeus) weakly inhibited S. aureus MurA (IC50 of 480 µM) but did not inhibit E. coli MurA. The antimicrobial activity of albocycline against resistant S. aureus strains was superior to that of vancomycin, preferentially inhibiting Gram-positive organisms. Albocycline was not toxic to human HepG2 cells in MTT assays. While these studies demonstrate that albocycline is a promising lead candidate against resistant S. aureus, taken together they suggest that MurA is not the primary target, and further work is necessary to identify the major biological target.

Total Synthesis of (-)-Albocycline.

The macrolactone natural product (-)-albocycline is a promising antibiotic candidate for the treatment of both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains. Herein we report a concise total synthesis of (-)-albocycline in 14 steps from commercially available methyl (R)-3-hydroxybutyrate. Novel key steps include the highly regio- and stereoselective reactions of chiral N-sulfinyl metallodienamines (NSMDs) with aldehydes and the Davis oxaziridine, in addition to the Horner-Wadsworth-Emmons olefination of N-sulfinyl imines.

Diastereoselective Hydroxylation of N-tert-Butanesulfinyl Imines with 2-(Phenylsulfonyl)-3-phenyloxaziridine (Davis Oxaziridine).

The diastereoselective α-hydroxylation of N-tert-butanesulfinyl metallodienenamine and metalloenamines with Davis oxaziridine affords α-hydroxy N-sulfinyl imines with 50-88% yield and up to 98:2 diastereomeric ratio. Dramatic changes in diastereoselectivity and stereoselectivity were observed by choice of metal bases. The mechanistic understanding for the switch in diastereoselectivity was assisted by DFT computational modeling, which suggests the facial approach is governed by aza-enolate geometry. A one-pot protocol for the asymmetric synthesis of 1,2-amino alcohols is described.

Domino Michael/Mannich Annulation Reaction of N-Sulfinyl Lithiodienamines.

The domino Michael/Mannich (DMM) annulation reaction between an N-sulfinyl lithiodienamine and an electrophilic alkene is developed for the synthesis of chiral 2-amino cyclohexenes, a key building block in asymmetric synthesis. The DMM reaction proceeds at low temperature while maintaining the stereochemical fidelity. The product functionalized amino cyclohexenes, here obtained in 55-82% yield with diastereomeric ratios as high as >19:1.