Tracking bacterial porin switching: A chemical biology approach

The World Health Organisation (WHO) identifies antimicrobial resistance (AMR) as one of the top 10 global threats to human health (http://www.who.int/). A recent analysis of the burden from AMR estimates that globally, 1.27 million deaths in 2019 could be directly attributed to AMR, and a further 4.95 million deaths were associated with AMR (Murray et al. 2022). The identification of molecular resistance mechanisms is therefore of great urgency for the development of novel treatment strategies and diagnostics.

The goal of this project is to understand how porin switching drives the development of AMR in the nosocomial pathogen Klebsiella pneumoniae, the causative agent of pneumonia and a WHO “priority pathogen”.

Porins are water-filled open channels in the outer membrane (OM) of Gram-negative bacteria that allow the passive transport of small, hydrophilic molecules across the OM. Individual bacteria possess up to 8-10 different porin-encoding genes, whose expression is finely regulated in response to environmental factors, including antibiotics.

Switching between different porins allows pathogens to modulate the permeability of their cell envelope. Porin switching has been linked to the stepwise increase in AMR and the phenomenon of “MIC creep”, which plays a decisive role in the gradual increase in global resistance. Although porins have been directly implicated in a new form of carbapenem resistance in Klebsiella pneumoniae, a detailed understanding of the factors that drive porin switching, and how this is linked to resistance development and bacterial pathogenicity, is currently lacking.

In this project, we will use computer-assisted design strategies and modern methods of organic synthesis to develop novel chemical tools for bacterial porin tracking. He/she will use these tools to identify critical environmental factors that drive porin switching in Klebsiella pneumoniae. These novel tools will also form the basis for the development of a novel, point-of-care diagnostic for resistant bacterial infections.

The project is a collaboration with the UK Health Security Agency (UKHSA) and will include placement opportunities at UKHSA.

Applicants should have a 1st or 2.1 honours degree (or equivalent) in a relevant subject. Relevant subjects include Chemistry, Chemical Biology, Pharmaceutical Sciences, Pharmacy, Biochemistry, or a closely related discipline. Students who have a 2.2 honours degree and a Master’s degree may also be considered, but the School reserves the right to shortlist for interview only those applicants who have demonstrated high academic attainment to date.

Postgraduate Research applicants must have applied to Queen’s, via the Direct Applications Portal. https://dap.qub.ac.uk/portal/user/u_login.php

Informal enquiries should be directed to [Email Address Removed]

The title of the studentship should be referenced in all correspondence.

The project is highly interdisciplinary and ideally suited for a student who wants to pursue a career in drug design and development. The student will receive in-depth training in a broad range of experimental techniques as relevant for drug discovery and medicinal chemistry, including computer-assisted probe design, advanced organic synthesis, chemical tool development, bacterial cell culture, protein mass spectrometry, bacterial proteomics, containment microbiology, and analysis of multi-drug resistant clinical pathogens.

The project is highly collaborative and will give the student exposure to different research environments, including placements at the UK Health Security Agency (UKHSA). The project will also provide an ideal opportunity for him/her to acquire transferable and generic skills such as time/project management and organisational skills, and experience in commercialization and science outreach.

It is anticipated that chemical probes developed in this project will create opportunities for knowledge transfer, translation, and commercialisation in the area of diagnostics development. The project will also offer an opportunity for the student to contribute to a range of outreach activities such as the regular delivery of science workshops for school children and lay audiences.