Inhibitors for the interaction site between translocase MraY and the lysis protein E from bacteriophage X174 as anti-Pseudomonas therapeutics
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
Programme overview:
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address important applied biomedical research questions in priority areas aligned with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.
Project overview:
The discovery of novel antimicrobial agents against antibiotic-resistant Gram-negative bacteria is an important clinical need, to combat growing antibiotic resistance and shortage of new therapies. Assembly of the bacterial cell wall peptidoglycan is a well-proven target for antibacterial action, by penicillins and glycopeptide antibiotics. Professor Bugg's research group has previously studied translocase enzyme MraY on the bacterial cell wall peptidoglycan biosynthetic pathway, and has identified a protein-protein interaction site between translocase enzyme MraY and lysis protein E from bacteriophage X174. This site can be targeted by peptides mimicking a motif Arg-Trp-x-x-Trp, which show antimicrobial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli.
The project will involve the chemical synthesis and biological testing of non-peptide compounds (peptidomimetics) that target this site, which are likely to have better properties as drug candidates. Compounds will be tested as MraY inhibitors using in vitro laboratory assays, and will be evaluated for antimicrobial activity against a range of bacterial strains, including antibiotic-resistant strains. The crystal structure of MraY will be used to carry out structure-based drug design (with industrial partner LifeArc), to refine inhibitor structures, and active compounds will be tested in Pseudomonas aeruginosa infection models.
The project will involve interdisciplinary training in chemical synthesis of drug candidates, enzyme purification and quantitative enzyme assays, computational drug design, and antimicrobial testing against clinically relevant antibiotic-resistant bacterial strains.
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address important applied biomedical research questions in priority areas aligned with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.
Project overview:
The discovery of novel antimicrobial agents against antibiotic-resistant Gram-negative bacteria is an important clinical need, to combat growing antibiotic resistance and shortage of new therapies. Assembly of the bacterial cell wall peptidoglycan is a well-proven target for antibacterial action, by penicillins and glycopeptide antibiotics. Professor Bugg's research group has previously studied translocase enzyme MraY on the bacterial cell wall peptidoglycan biosynthetic pathway, and has identified a protein-protein interaction site between translocase enzyme MraY and lysis protein E from bacteriophage X174. This site can be targeted by peptides mimicking a motif Arg-Trp-x-x-Trp, which show antimicrobial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli.
The project will involve the chemical synthesis and biological testing of non-peptide compounds (peptidomimetics) that target this site, which are likely to have better properties as drug candidates. Compounds will be tested as MraY inhibitors using in vitro laboratory assays, and will be evaluated for antimicrobial activity against a range of bacterial strains, including antibiotic-resistant strains. The crystal structure of MraY will be used to carry out structure-based drug design (with industrial partner LifeArc), to refine inhibitor structures, and active compounds will be tested in Pseudomonas aeruginosa infection models.
The project will involve interdisciplinary training in chemical synthesis of drug candidates, enzyme purification and quantitative enzyme assays, computational drug design, and antimicrobial testing against clinically relevant antibiotic-resistant bacterial strains.
People |
ORCID iD |
| Timothy Bugg (Primary Supervisor) | |
| Julia Fairbairn (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/R015910/1 | 01/10/2018 | 30/09/2026 | |||
| 2269737 | Studentship | MR/R015910/1 | 01/10/2019 | 03/04/2024 | Julia Fairbairn |