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Jackson, Laurie K., Dailey, Tammy A., Anderle, Brenden, Warren, Martin J. 
ORCID: https://orcid.org/0000-0002-6028-6456, Bergonia, Hector A., Dailey, Harry A. and Phillips, John D.
(2023)
Exploiting differences in heme biosynthesis between bacterial species to screen for novel antimicrobials.
Biomolecules, 13 (10).
ISSN 2218-273X
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Abstract
The final three steps of heme biogenesis exhibit notable differences between di- and mono-derm bacteria. The former employs the protoporphyrin-dependent (PPD) pathway, while the latter utilizes the more recently uncovered coproporphyrin-dependent (CPD) pathway. In order to devise a rapid screen for potential inhibitors that differentiate the two pathways, the genes associated with the protoporphyrin pathway in an Escherichia coli YFP strain were replaced with those for the CPD pathway from Staphylococcus aureus (SA) through a sliding modular gene replacement recombineering strategy to generate the E. coli strain Sa-CPD-YFP. Potential inhibitors that differentially target the pathways were identified by screening compound libraries against the YFP-producing Sa-CPD-YFP strain in comparison to a CFP-producing E. coli strain. Using a mixed strain assay, inhibitors targeting either the CPD or PPD heme pathways were identified through a decrease in one fluorescent signal but not the other. An initial screen identified both azole and prodigiosin-derived compounds that were shown to specifically target the CPD pathway and which led to the accumulation of coproheme, indicating that the main target of inhibition would appear to be the coproheme decarboxylase (ChdC) enzyme. In silico modeling highlighted that these inhibitors are able to bind within the active site of ChdC.
| Item Type: | Article |
|---|---|
| Additional Information: | Data Availability Statement: The data will be made available from the CCEH.io website and strains will be made available once an institutional MTA is signed with the University of Utah. Funding Information: This research was funded by NIH-NIDDK, grant number DK202503 and DK110858 to J.D.P. and DK096051 to H.A.D., and the BBSRC Institute Strategic Programme Food Microbiome and Health BB/X011054/1 and its constituent project BBS/E/F/000PR13631 to MJW. |
| Uncontrolled Keywords: | antimicrobial,diderm,heme biosynthesis,monoderm,screen,biochemistry,molecular biology ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
| Faculty \ School: | Faculty of Science Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Centres > Population Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 29 Oct 2024 15:30 |
| Last Modified: | 13 Nov 2024 17:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/97347 |
| DOI: | 10.3390/biom13101485 |
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