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Applying BICePs and MSMs to understand the action of a macrolide antibiotic

In new collaborative work with the AndradeLeimkuhler GrimesDunman and Valentine groups, we have brought our cutting-edge computational methods to bear on the problem of understanding the effects of the macrolide antibiotic albocycline on Staphylococcus aureus, bacteria attributed as a major source of antibiotic resistance.

Based on initial characterizations of albocycline, which suggested a mechanism in which the molecule targets inhibits of peptidoglycan biosynthesis of the bacterial cell wall, our manuscript explores the inhibition of an enzyme called MurA by albocycline.   Experimental studies from the Grimes group showed that albocycline inhibits MurA.  To model the interaction between albocycline MurA, we used our BICePs algorithm to combine QM/REMD modeling and NMR restraints to determine the likely structure of albocycline in solution.   We then performed distributed simulations of the MurA enzyme on Folding@home, generating a large collection of receptor conformations that we could use to homology-model related enzymes and perform computational docking.  Intriguingly, the ensemble-docking studies correctly predicted the relative affinities of albocycline to S. aureus MurA, S. aureus MurZ and E. coli MurA.   However, we also find the albocycline is a more potent antibiotic than can be explained by its affinity for MurA alone, suggesting another target, which may be discovered by future screening of resistance mutants.  

To learn more, check out our full paper in Bioorganic & Medicinal Chemistry:Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus. Liang, Hai; Zhou, Guangfeng; Ge, Yunhui; D’Ambrosio, Elizabeth; Eidem, Tess; Blanchard, Catlyn; Louka, Cindy; Chatare, Vijay; Dunman, Paul; Valentine, Ann; Voelz, Vincent; Grimes, Catherine; Andrade, Rodrigo, Accepted, Bioorganic & Medicinal Chemistry (2018). doi:10.1016/j.bmc.2018.05.017


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