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Bacterial ABC transporters involved in antibiotic resistance and sensing

Primary Supervisor: Dr. Allister Crow, School of Life Sciences

Secondary supervisors: Dr. Susanne Gebhard, Bath; Professor David Roper, Warwick

PhD project title: Bacterial ABC transporters involved in antibiotic resistance and sensing

University of Registration: University of Warwick

Project outline:

Type VII ABC transporters are a superfamily of ATP-powered membrane proteins that function in bacterial antibiotic resistance, toxin secretion, cell division and membrane biogenesis [1,2,3]. The archetype of the superfamily is MacB – a protein involved in antibiotic resistance and protein secretion [1]. In E. coli, MacB operates as part of a tripartite efflux pump that spans the cell envelope and drives its substrates (antibiotics or toxins) from the periplasm to the cell exterior [1,2]. MacB has a novel ABC transporter fold and uses an unusual ‘mechanotransmission mechanism’ to couple cytoplasmic ATP hydrolysis with work in the periplasmic space [1]. Similar mechanisms are predicted to be at play in other Type VII ABC transporters [1,2], including cell division signalling complex FtsEX [2] and the lipoprotein trafficking machinery, LolCDE [3], but the biology of many related systems remains underexplored.

This project focusses on the BceAB subfamily of Type VII ABC transporters that provide resistance to membrane-attacking antibiotics such as bacitracin [4]. BceAB proteins are expected to be structurally similar to MacB but do not form tripartite pumps. The mechanism by which BceAB-like proteins confer resistance is not yet clear, but may involve pulling antibiotics from out of the bacterial membrane or prising them away from their lipid targets. BceAB can also sense the presence of antibiotics and initiate an intracellular signalling cascade that upregulates its own production [4]. The mechanism by which BceAB proteins sense, and provide resistance to, antibiotics is of fundamental scientific interest.

This project seeks to further characterise BceAB-like proteins by obtaining structural and functional information that can be used to understand how they work.

The project will suit a student interested in microbiology, antibiotic resistance and structural biology. Techniques will include protein purification, X-ray crystallography, and microbiological assays.

Student input in shaping the project is encouraged. We urge students interested in the project to get in contact at earliest possible opportunity.

References:

  1. [Crow et al. (2017) Structure and mechanotransmission mechanism of the MacB ABC transporter superfamilyProceedings of the National Academy of Sciences of the United States of America 114 (47) 12572
  2. Greene et al. (2018) Antibiotic Resistance Mediated by the MacB ABC Transporter Family: A Structural and Functional Perspective Frontiers in Microbiology(9) 950
  3. Kaplan et al. (2018) Insights into bacterial lipoprotein trafficking from a structure of LolA bound to the LolC periplasmic domain Proceedings of the National Academy of Sciences of the United States of America 115 (31) E7389
  4. Dintneret al. (2014) A sensory complex consisting of an ATP-binding cassette transporter and a two-component regulatory system controls bacitracin resistance in Bacillus subtilis Journal of Biological Chemistry 289 (40) 27899-27910

BBSRC Strategic Research Priority: Understanding the Rules of Life: Structural Biology

Techniques that will be undertaken during the project:

  • X-ray crystallography
  • Structural biology
  • Antibiotic susceptibility testing
  • DNA cloning and site-directed mutagenesis

Contact: Dr Allister Crow, University of Warwick