Structure-guided microbial targeting of antistaphylococcal prodrugs

Miller, Justin J.; Shah, Ishaan T.; Hatten, Jayda; Barekatain, Yasaman; Mueller, Elizabeth A.; Moustafa, Ahmed M.; Edwards, Rachel L.; Dowd, Cynthia S.; Planet, Paul J.; Muller, Florian L.; Jez, Joseph M.; Odom John, Audrey R.

doi:10.7554/elife.66657

Structure-guided microbial targeting of antistaphylococcal prodrugs

Journal Article · Mon Jul 19 00:00:00 EDT 2021 · eLife

DOI:https://doi.org/10.7554/elife.66657· OSTI ID:1812909

^[1]; Shah, Ishaan T. ^[2]; Hatten, Jayda ^[2]; Barekatain, Yasaman ^[3]; ^[4]; ^[5]; Edwards, Rachel L. ^[2]; Dowd, Cynthia S. ^[6]; Planet, Paul J. ^[5]; Muller, Florian L. ^[3]; Jez, Joseph M. ^[4]; ^[7]

Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Pediatrics; Washington Univ., St. Louis, MO (United States). Dept. of Biology
Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Pediatrics
Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States). Dept. of Cancer Systems Imaging
Washington Univ., St. Louis, MO (United States). Dept. of Biology
Univ. of Pennsylvania and Children’s Hospital of Philadelphia, PA (United States). Dept. of Pediatrics. Perelman School of Medicine
George Washington Univ., Washington, DC (United States). Dept. of Chemistry
Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Pediatrics. Dept. of Molecular Microbiology; Univ. of Pennsylvania and Children’s Hospital of Philadelphia, PA (United States). Dept. of Pediatrics. Perelman School of Medicine

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1812909

Journal Information:: eLife, Journal Name: eLife Vol. 10; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
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Structure-guided microbial targeting of antistaphylococcal prodrugs

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