Structure-guided microbial targeting of antistaphylococcal prodrugs
- Washington University School of Medicine, United States
- The University of Texas MD Anderson Cancer Center, United States
- Washington University in St Louis, United States
- Children's Hospital of Philadelphia, United States
- The George Washington University, United States
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 anti-staphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.
Data availability
Sequencing data and structure data is provided in the manuscript and deposited on the NCBI BioProject database (PRJNA648156) or in the protein data bank (FrmB accession code 7L0A, GloB accession code 7L0B).
-
Understanding Staphylococcus aureus resistance to POM-HEXNCBI BioProject database, PRJNA648156.
Article and author information
Author details
Elizabeth A Mueller
Audrey R Odom John
Funding
National Institutes of Health (R01 AI103280; R21 AI123808; R21 AI130584)
- Audrey R Odom John
National Center for Research Resources (UL1 RR024992)
- Joseph Jez
Burroughs Wellcome Fund (PATH)
- Audrey R Odom John
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Miller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,236
- views
-
- 323
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Structure-guided microbial targeting of antistaphylococcal prodrugs
eLife 10:e66657.
https://doi.org/10.7554/eLife.66657
Further reading
-
- Biochemistry and Chemical Biology
- Stem Cells and Regenerative Medicine
Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling. In this study, we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors and find that while they express a near-identical set of proteins, they show consistent quantitative differences in the abundance of a subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs, with increased abundance of cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins. Prominent changes detected in proteins involved in mitochondrial metabolism correlated with enhanced mitochondrial potential, shown using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins, including growth factors and proteins involved in the inhibition of the immune system. The data indicate that reprogramming of fibroblasts to hiPSCs produces important differences in cytoplasmic and mitochondrial proteins compared to hESCs, with consequences affecting growth and metabolism. This study improves our understanding of the molecular differences between hiPSCs and hESCs, with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications.
