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The cell envelope of bacteria as a target for chelant and antibiotic combinations


Project Description

Bacterial metal and antibiotic resistance are increasingly recognised as processes that evolve in parallel. Although not well-characterised, co-resistance is frequently associated with cellular import and export mechanisms. Indeed, some antibiotics are actively transported to their intracellular targets as metal complexes. Hence disrupting the uptake of both metals and antibiotics, either separately or together, offers significant potential to combat increasingly drug-resistant pathogens. This project emerges from successful efforts, in partnership with Procter & Gamble (P&G), to deprive bacterial pathogens of essential metals using metal chelants with differing selectivities. To help determine the mode of action of two chelants with affinities for different metallic species, we isolated chelant-resistant mutants of two bacterial species and identified chromosomal changes from the resulting strains. Significantly, the alterations primarily affect cell surface molecules, membrane-bound transporters and peptidoglycan metabolism, rather than the anticipated metal uptake systems. Interestingly, improved resistance to certain antibiotics was also evident in several of the mutants. Moreover, treating bacteria with combinations of chelants and antibiotics identified synergistic, additive and indifferent effects. The wild-type and mutant derivatives of these bacteria therefore provide an excellent opportunity to probe the relationship between antibiotics, metal chelation and cell envelope architecture.

This PhD project offers an outstanding training opportunity in molecular, biochemical and biophysical techniques at the biology-chemistry interface. Training will be provided in handling microbes and examining their sensitivity to combinations of antibiotics and chelants. Analysis of cellular responses to metal starvation will be characterised, in parallel with the characterisation of changes in peptidoglycan, surface charge and envelope permeability. You will also gain expertise in super-resolution and electron microscopy techniques to visualise damaged bacterial cell membranes. The project offers significant potential to revitalise existing antibiotics for wound treatment in both medical and veterinary contexts. It will also contribute to the commercial development of chelants as additives in formulations relevant to P&G, giving insight and experience of working alongside industry suitable for an academic or industrial research career.

HOW TO APPLY
Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to


Funding Notes

This is a 4 year BBSRC CASE studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Coordination of capsule assembly and cell wall biosynthesis in Staphylococcus aureus. Nat Commun., 2019, 10: 1404.

A specialized MreB-dependent cell wall biosynthetic complex mediates the formation of stalk-specific peptidoglycan in Caulobacter crescentus. PLoS Genet., 2019, 15: e1007897.

Plasticity of Escherichia coli cell wall metabolism promotes fitness and antibiotic resistance across environmental conditions. eLife, 2019, 8: e40754.

On the antibacterial activity of azacarboxylate ligands: lowered metal ion affinities for some bis-amide derivatives of EDTA do not necessarily mean reduced activity. Chem. Eur. J., 2018, 24: 7137-7148.

Copper inhibits peptidoglycan LD-transpeptidases suppressing -lactam resistance due to by-pass of penicillin-binding proteins. Proc. Nat. Acad. Sci. USA, 2018, 115: 10786-10791.

Z-ring membrane anchors associate with cell wall synthases to initiate bacterial cell division. Nat. Comm., 2018, 9: 5090.

Induced conformational changes activate the peptidoglycan synthase PBP1B. Mol. Microbiol., 2018, 110: 335-356.

Exploring the links between peptoid antibacterial activity and toxicity. Med. Chem. Comm., 2017, 8: 886-896

The redundancy of peptidoglycan carboxypeptidases ensures robust cell shape maintenance in Escherichia coli. mBio, 2016, 7: e00819-16.

Glycosylated nanoparticles as efficient antimicrobial delivery agents. Biomacromolecules, 2016, 17: 2672-2679.

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