Dissecting an antibiotic resistance network in the hospital 'superbug' Enterococcus faecalis

Hospital-acquired infections with Enterococcus bacteria impose a significant public health burden, with ca. 5000
cases of bacteraemia reported in the UK each year and an estimated mortality rate of 20%. Enterococci form a
natural component of the human gut microflora. Infections usually arise following treatment of a patient for an
unrelated infection, and this is because enterococci possess a striking degree of intrinsic drug resistance. While most
bacteria within a patient receiving antibiotics die, enterococci can often thrive, which in turn sharply increases the risk
for enterococcal infections. Past studies of drug resistance in enterococci have mostly focussed on the antibiotic
vancomycin, which is commonly used to treat such infections, and we now have an excellent understanding of the
specific resistance mechanisms involved. However, we know surprisingly little about the molecular basis for the
intrinsic resistance of the bacteria against many other antibiotics. Considering that this generic resistance is what
provides enterococci with the opportunity to cause disease, addressing this question is timely and highly relevant.
This studentship project is aimed at gaining a molecular and systems level understanding of the response of
Enterococcus faecalis to antibiotics that target the cell envelope. Building on previous work from the Gebhard lab and
the literature, the candidate will identify candidate regulators and resistance genes, and experimentally investigate
the signalling pathways that control the cell envelope stress response of E. faecalis. To maximise success and
identify the complete regulatory network, the student will apply a two-pronged approach combining random and
targeted mutagenesis. Candidate regulators will be confirmed by loss of target gene regulation and resistance. We
have recently shown that antibiotic resistance can be organised in complex hierarchical networks that utilise active
redundancy between individual resistance determinant s to compensate for failure of individual components. The
student will therefore analyse any identified regulators for cross-communication and hierarchical organisation using
biochemistry, genetics and mathematical modelling. The broad expertise of the supervisory team will ensure crosscutting
training for the candidate in both practical and theoretical state-of-the-art methodology. A detailed
understanding of the systems level organisation of the antibiotic stress response of E. faecalis may ultimately allow
the identification of an Achilles' heel that can be exploited for the development of targeted therapeutic strategies.
Contacts are in place to a team of clinicians in Denmark who can test the relevance of the findings, e.g. by examining
their epidemiological data for prevalence and potential pathoadaptive mutations in the key regulators, which will
provide immediate application of this study in a clinical context.