The bacterial protein translocation machinery: a target for new strategies against antimicrobial resistance

Bacterial resistance to antibiotics is a major problem affecting millions of people across the world. This
severely affects treatment of bacterial infections as strains are emerging that are totally resistant to
all clinically used antibiotics. This problem is termed Antimicrobial Resistance (AMR). If its spread
continues un-checked the number of people dying from microbial infections will rise to catastrophic
proportions. Routine operations will become high risk, as there will be few or no options to treat
resulting infections. Similarly, cancer chemotherapy and organ transplants will become more
problematic without antibiotics to protect immune-compromised patients. Tackling AMR requires the
development of new antibiotics, particularly those that function by targeting different bacterial
mechanisms than current antibiotics. These new medicines will circumvent current resistant
mechanisms being used by drug resistant bacteria. Also, new medicines which reverse resistance to
current antibiotics should be developed, allowing for improved effectiveness of current antibiotics.
This project will explore a novel strategy against this problem. A common mechanism that bacteria
deploy to resist antibiotics is the secretion of beta-lactamases. Our group has considerable expertise
and resources focussed on the analysis of bacterial protein secretion - the Sec-machinery. We aim to
exploit this knowledge towards the specific analysis of the transport of the beta-lactamases, which
are exported via this route. The project will involve the development of in vivo and in vitro secretion
assays that report on the transport of a range of beta-lactamases. Once established we will undertake
a comprehensive analysis of the mechanism of this process and the specific requirements for betalactamase
secretion.
The project is multi-disciplinary, involving the application of a spectrum of technologies ranging from
microbiological (Avison) to functional reconstitution of membrane systems for biochemical and
biophysical analysis (Collinson) - for an excellent training opportunity.
The development of drugs against the secretion of beta-lactamases would be particularly valuable as
they would act against a wide range of resistant mechanisms and thus re-potentiate those antibiotics
that have been rendered impotent by emergent strains. We already have a collaboration with the
Dundee Drug Discovery unit for the deployment of high throughput screens against the general
secretion process. Therefore, this studentship presents an excellent opportunity to target the features
of the transport machinery pertinent to AMR