21102-49-8Relevant articles and documents
Synthetic group A streptogramin antibiotics that overcome Vat resistance
Biel, Justin T.,Borrelli, Kenneth,Brilot, Axel F.,Chaires, Hector A.,Chesneau, Olivier,Chow, David,Fraser, James S.,Jacobson, Matthew P.,Ji, Kaijie,Lee, D. John,Li, Qi,Murray, Beverly,Park, Jesslyn E.,Pellegrino, Jenna,Seiple, Ian B.,Shinabarger, Dean,Tran, Arthur A.,Wang, Ruoxi,Wolfe, Cindy,Zhang, Na,van Zundert, Gydo,Mühle, Estelle
, p. 145 - 150 (2020)
Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics1. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins2, potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome3. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed2. Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.
STREPTOGRAMIN COMPOSITIONS AND THE USE THEREOF
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, (2020/12/30)
Disclosed herein, inter alia, are streptogramin compounds, compositions, and methods of use thereof. A method of treating an infectious disease, the method including administering to a subject in need thereof an effective amount of a compound described herein.
METHODS OF MAKING STREPTOGRAMIN COMPOSITIONS AND THE USE THEREOF
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, (2019/02/15)
Disclosed herein, inter alia, are methods of making and using streptogramin compositions.
Modular, Scalable Synthesis of Group A Streptogramin Antibiotics
Li, Qi,Seiple, Ian B.
, p. 13304 - 13307 (2017/10/05)
Streptogramin antibiotics are used clinically to treat multidrug-resistant bacterial infections, but their poor physicochemical properties and narrow spectra of activity have limited their utility. New methods to chemically modify streptogramins would enable structural optimization to overcome these limitations as well as to combat growing resistance to the class. Here we report a modular, scalable synthesis of group A streptogramin antibiotics that proceeds in 6-8 linear steps from simple chemical building blocks. We have applied our route to the synthesis of four natural products in this class including two that have never before been accessed by fully synthetic routes. We anticipate that this work will lead to the discovery of new streptogramin antibiotics that overcome previous limitations of the class.
Total synthesis of (-)-virginiamycin m2: Application of crotylsilanes accessed by enantioselective Rh(II) or Cu(I) promoted carbenoid Si-H insertion
Wu, Jie,Panek, James S.
experimental part, p. 9900 - 9918 (2012/03/08)
A stereoselective synthesis of the antibiotic (-)-virginiamycin M 2 is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si-H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1-C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne-alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,-E)-diene. An underutilized late-stage SmI2-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product (Figure presented).
Total synthesis of (-)-virginiamycin M2 using second-generation vinylogous urethane chemistry
Schlessinger,Li
, p. 3301 - 3302 (2007/10/03)
Antibiotics known as the virginiamycins consist of two groups-polyunsaturated macrolactones (type A) and peptidic macrolactones (type B). Mixtures of type A and type B virginiamycins exhibit very high potency against a variety of bacteria. Total syntheses
