Structure-guided microbial targeting of antistaphylococcal prodrugs

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 hydroly...

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Autores principales:	Justin J Miller, Ishaan T Shah, Jayda Hatten, Yasaman Barekatain, Elizabeth A Mueller, Ahmed M Moustafa, Rachel L Edwards, Cynthia S Dowd, Geoffrey C Hoops, R Jeremy Johnson, Paul J Planet, Florian L Muller, Joseph M Jez, Audrey R Odom John
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	Staphylococcus aureus antibacterial prodrug drug discovery esterase Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/17f733fe025245b6a2dbe45ff732edb9
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spelling	oai:doaj.org-article:17f733fe025245b6a2dbe45ff732edb92021-11-25T12:59:08ZStructure-guided microbial targeting of antistaphylococcal prodrugs10.7554/eLife.666572050-084Xe66657https://doaj.org/article/17f733fe025245b6a2dbe45ff732edb92021-07-01T00:00:00Zhttps://elifesciences.org/articles/66657https://doaj.org/toc/2050-084XCarboxy 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.Justin J MillerIshaan T ShahJayda HattenYasaman BarekatainElizabeth A MuellerAhmed M MoustafaRachel L EdwardsCynthia S DowdGeoffrey C HoopsR Jeremy JohnsonPaul J PlanetFlorian L MullerJoseph M JezAudrey R Odom JohneLife Sciences Publications LtdarticleStaphylococcus aureusantibacterialprodrugdrug discoveryesteraseMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus antibacterial prodrug drug discovery esterase Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	Staphylococcus aureus antibacterial prodrug drug discovery esterase Medicine R Science Q Biology (General) QH301-705.5 Justin J Miller Ishaan T Shah Jayda Hatten Yasaman Barekatain Elizabeth A Mueller Ahmed M Moustafa Rachel L Edwards Cynthia S Dowd Geoffrey C Hoops R Jeremy Johnson Paul J Planet Florian L Muller Joseph M Jez Audrey R Odom John Structure-guided microbial targeting of antistaphylococcal prodrugs
description	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.
format	article
author	Justin J Miller Ishaan T Shah Jayda Hatten Yasaman Barekatain Elizabeth A Mueller Ahmed M Moustafa Rachel L Edwards Cynthia S Dowd Geoffrey C Hoops R Jeremy Johnson Paul J Planet Florian L Muller Joseph M Jez Audrey R Odom John
author_facet	Justin J Miller Ishaan T Shah Jayda Hatten Yasaman Barekatain Elizabeth A Mueller Ahmed M Moustafa Rachel L Edwards Cynthia S Dowd Geoffrey C Hoops R Jeremy Johnson Paul J Planet Florian L Muller Joseph M Jez Audrey R Odom John
author_sort	Justin J Miller
title	Structure-guided microbial targeting of antistaphylococcal prodrugs
title_short	Structure-guided microbial targeting of antistaphylococcal prodrugs
title_full	Structure-guided microbial targeting of antistaphylococcal prodrugs
title_fullStr	Structure-guided microbial targeting of antistaphylococcal prodrugs
title_full_unstemmed	Structure-guided microbial targeting of antistaphylococcal prodrugs
title_sort	structure-guided microbial targeting of antistaphylococcal prodrugs
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/17f733fe025245b6a2dbe45ff732edb9
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Structure-guided microbial targeting of antistaphylococcal prodrugs

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