Barekatain Y

References (1)

Title : Structure-guided microbial targeting of antistaphylococcal prodrugs - Miller_2021_Elife_10_e66657
Author(s) : Miller JJ , Shah IT , Hatten J , Barekatain Y , Mueller EA , Moustafa AM , Edwards RL , Dowd CS , Hoops GC , Johnson RJ , Planet PJ , Muller FL , Jez JM , Odom John AR
Ref : Elife , 10 : , 2021
Abstract : Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. These studies will enable structure-guided design of antistaphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.
ESTHER : Miller_2021_Elife_10_e66657
PubMedSearch : Miller_2021_Elife_10_e66657
PubMedID: 34279224
Gene_locus related to this paper: staau-SA2422