Broadening the spectrum of antibacterial drugs to tackle multi-drug resistant Gram-negative pathogens

Antibiotics make possible the treatment and cure of life-threatening bacterial infections and have added over a decade to average human lifespan. Unfortunately, the utility of these drugs is being rapidly eroded as pathogenic bacteria evolve to resist their effects; in 2019, antimicrobial resistance (AMR) killed ~1.3 million people worldwide, and this figure is set to rise to 10 million by 2050. The situation is particularly grave in the case of Gram-negative (G-VE) pathogens, which, in contrast to Gram-positive (G+VE) bacteria, are intrinsically insusceptible to many classes of antibacterial drug owing to the permeability barrier presented by the outer membrane and the action of efflux transporters that pump drugs out of the cell. <br /> <br /> This project will develop much-needed novel anti-G-VE agents through rational, structure-guided modification of established antibacterial drug classes that currently only show clinically useful activity against G+VE bacteria. Although analogue improvement of antibacterial drugs is a proven strategy, it has not typically been successful in expanding the activity of anti-G+VE agents to encompass G-VEs; however, it represents a potentially powerful approach in this context that could circumvent many of the confounders encountered in discovery programmes and dramatically shorten the lead time to new drugs. Based on exciting proof of principle in very recent (as yet unpublished) work from our joint medicinal chemistry-biology effort, we have successfully undertaken rational optimisation of intracellular accumulation and target binding to build potent anti-G-VE activity into a drug class that previously showed none - our lead compound is now undergoing evaluation of therapeutic efficacy in vivo.

<p>The present study will seek to further increase the anti-GVE potency of the drug class in question, as well as extending this powerful approach to other clinically deployed classes that possess untapped potential for expansion of antibacterial spectrum (of which there are several). We will exploit our structural and mechanistic understanding of antibacterial drug targets - and of the biological processes influencing antibiotic accumulation inside G-VE bacteria - to design and synthesise new analogues of known classes. The resulting compounds will undergo extensive biological evaluation&nbsp;<em>in vitro</em>&nbsp;and&nbsp;<em>in vivo</em>&nbsp;to assess their antibacterial potency/ efficacy against a range of G-VE pathogens, and to confirm improved target binding and intracellular accumulation.</p> <p>Collectively, this project will generate new knowledge, insight and antibacterial molecules, all of which can contribute towards addressing the growing global challenge of AMR. The appointed student will benefit from cutting-edge, multidisciplinary training in medicinal chemistry, molecular bacteriology and antibiotic discovery.</p> <p>Please see our websites for more information about the work that we do, and links to our publications:</p> <p><a href="https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/119/professor-alex-o-neill" rel="noopener noreferrer" target="_blank">https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/119/professor-alex-o-neill</a></p> <p><a href="https://eps.leeds.ac.uk/chemistry/staff/5234/dr-martin-mcphillie" rel="noopener noreferrer" target="_blank">https://eps.leeds.ac.uk/chemistry/staff/5234/dr-martin-mcphillie</a></p> <p><a href="https://eps.leeds.ac.uk/chemistry/staff/4172/professor-colin-fishwick" rel="noopener noreferrer" target="_blank">https://eps.leeds.ac.uk/chemistry/staff/4172/professor-colin-fishwick</a></p> <p>References</p> <p>These references provide a general flavour of our research on antibacterial drug discovery and AMR - they do not describe work directly related to this project.</p> <ul> <li>Galarion LH, Mitchell JK, Randall CP, O&#39;Neill AJ (2023) An extensively validated whole-cell biosensor for specific, sensitive and high-throughput detection of antibacterial inhibitors targeting cell-wall biosynthesis. Journal of Antimicrobial Chemotherapy, 78: 646-655</li> <li>Mohamad M, Nicholson D, Saha CK, Hauryliuk V, Edwards TA, Atkinson GC, Ranson NA, O&rsquo;Neill AJ (2022). Sal-type ABC-F proteins: intrinsic and common mediators of pleuromutilin resistance by target protection in staphylococci. Nucleic Acids Research, 50: 2128-2142</li> <li>Orritt KM, Feng L, Newell JF, Sutton JN, Grossman S, Germe T, Abbott LR, Jackson HL, Bury BKL, Maxwell A, McPhillie MJ, Fishwick CWG (2022) De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region. RSC Medicinal Chemistry, 831-839 13.7</li> <li>Lang PA, Parkova A, Leissing TM, Calvopi&ntilde;a K, Cain R, Krajnc A, Panduwawala TD, Philippe J, Fishwick CWG, Trapencieris P, Page MGP, Schofield CJ, Brem J (2020) Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C &beta;-Lactamase from Escherichia coli, Biomolecules. 10.6<br /> &nbsp;</li> </ul>

<p>To apply for this project opportunity applicants should complete an <a href="https://biologicalsciences.leeds.ac.uk/research-degrees/doc/how-to-apply">online application form</a> and attach the following documentation to support their application.&nbsp;</p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks</li> <li>Evidence that you meet the University&#39;s minimum English language requirements (if applicable)</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Biological Sciences as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p>This project is open to applicants who have the funding to support their own studies or who have a sponsor who will cover these costs.&nbsp;</p>

<p>For information about the application process please contact the Faculty Admissions Team:</p> <p>e: <a href="mailto:fbsgrad@leeds.ac.uk">fbsgrad@leeds.ac.uk</a></p>