Elucidating the molecular mechanisms of intrinsic antibiotic resistance in bacterial pathogens

Antibiotics make possible the treatment and cure of life-threatening bacterial infections and have added over a decade to the 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 O’Neill laboratory at Leeds is actively pursuing several complementary approaches to better understand and address this phenomenon, with a major focus on understanding the mechanisms that allow ’superbugs’ to resist the effects of antibiotics.

<p>Studies into antibiotic resistance mechanisms have typically focused on&nbsp;<em>acquired</em>&nbsp;resistance &ndash; in other words, evolved traits that become selected in bacteria by antibiotic exposure. However, many bacteria are inherently resistance to particular antibiotic classes, a phenomenon known as intrinsic resistance. The latter is currently under-studied, though it has become clear that analysis of&nbsp;such intrinsic resistance mechanisms can offer profound fundamental insights into the biology of AMR and provide valuable strategic intelligence to inform the discovery of newer generations of antibiotics.&nbsp;This studentship will investigate the genetic and biochemical basis for intrinsic resistance to a variety of important antibacterial drugs in key pathogenic bacteria, employing a suite of cutting-edge approaches in molecular biology to do so. Please see reference I below for an example of intrinsic resistance and the kinds of tools we have at our disposal to study it.</p> <p><em>Please see the O&rsquo;Neill lab website for more information about what we do, and links to our published work:</em></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>References</p> <ul> <li>I. 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>II. Crowe-McAuliffe C, Murina V, Turnbull KJ, Kasari M, Mohamad M, Polte C, Takada H, Vaitkevicius K, Johansson J, Ignatova Z, Atkinson GC, O&rsquo;Neill AJ, Hauryliuk V, Wilson DN (2021). Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. Nature Communications, 12: 3577</li> <li>III. Wilson DN, Hauryliuk V, Atkinson GC, O&#39;Neill AJ (2020). Target protection as a key antibiotic resistance mechanism. Nature Reviews Microbiology, 18: 637-648</li> <li>IV. Kime L, Randall CP, Banda FI, Coll F, Wright J, Richardson J, Empel J, Parkhill J, O&#39;Neill AJ. 2019. Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure. mBio, 10: e01755-19<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>