Polyvalent Multifunctional Nanoparticles to Address Resistance Bacteria

The emergence of antibiotic resistant bacteria, e.g. methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) has created a major global health problem, affecting millions of patients worldwide.[1] For example, vancomycin (Van) is a potent antibiotic for treating Gram-positive bacterial infection. Van specifically binds to bacteria cell wall mucopeptide terminal D-Ala-D-Ala residues by forming five H-bonds which sterically prevents cell-wall cross-linking and inhibit microbial growth. Mutation of a single amino acid residue from D-Ala-D-Ala to D-Ala-D-Lac in VRE deletes a single H-bond, reducing its Van binding affinity by ~1000 fold and rendering Van therapeutically useless.[2] By linking two Vans together, Van dimers have shown enhanced potency against VRE,[3] although its potency still need to be further improved to meet the clinical need.<br /> <br /> This project aims to develop a polyvalent multifunctional nanoparticle (PMN) strategy to address the bacterial antibiotic resistance problem. Using Van as a model antibiotic, we will create multivalent display of Van on the nanoparticle surface which can bind simultaneously to multiple D-Ala-D-Lac residues on the VRE surface, greatly enhance its binding affinity and overcome VREs resistance mechanism. Meanwhile, the unique chemico-/physical properties (e.g. photothermal for nanorod)[4] and intrinsic anti-bacterial property of nanoparticles (e.g. silver)[5] will be further combined to offer potent multi-modal anti-bacterial action.

<p>A major limitation of current antibacterial nanomaterial research has been too focused on pursuing antibacterial potency only without or little consideration of their stability and interactions with biological media and renal clearance. These are key requiremens for real world application and clinical approval. As a result, most current antibacterial nanomaterials have little proposet of being translated into useful drugs despite high antibacterial potency in vitro. Here we will address this problem by balancing these needs at the begining of our antibacterial nanomaterials design, greatly enhancing their chances for clinical impact.</p> <p>Specifically, this project will,</p> <p>1) synthesise and characterise lipoic acid-PEG or zwitterionic based multi-functional ligands to enhance nanoparticle stability and reduce non-specific interactions with serum proteins and other biological compotents;</p> <p>2) synthesise and characterise nanoparticles of different sizes to allow for renal clearance;</p> <p>3) investigate how particle size, shape and surface chemistry determine its anti-bacterial potency;</p> <p>4) prepare polyvalent Van-nanoparticles and evaluate the valency, shape and size-dependence on anti-bacterial potency;</p> <p>5) investigate the potency of combined multimodal treatment against resistant bacteria (e.g. VRE, with Prof. Alex O’Neil, FBS).</p>

<p>Formal applications for research degree study should be made online through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University's website</a>. Please state clearly in the Planned Course of Study that you are applying for <em><strong>PHD Chemistry FT</strong></em> in the research information section that the research degree you wish to be considered for is <em><strong>Polyvalent Multifunctional Nanoparticles to Address Resistance Bacteria</strong></em> as well as Prof.<a href="https://physicalsciences.leeds.ac.uk/staff/199/professor-dejian-zhou"> Dejian Zhou</a> as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p style="margin-bottom:11px"><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> <p class="MsoNoSpacing">Applications will be considered on an ongoing basis.  Potential applicants are strongly encouraged to contact the supervisors for an informal discussion before making a formal application.  We also advise that you apply at the earliest opportunity as the application and selection process may close early, should we receive a sufficient number of applications or that a suitable candidate is appointed.</p> <p>Please note that you must provide the following documents at the point you submit your application:</p> <ul> <li>Full Transcripts of all degree study or if in final year of study, full transcripts to date</li> <li>Personal Statement outlining your interest in the project</li> <li>CV</li> <li>Funding information including any alternative sources of funding that you are applying for or if you are able to pay your own fees and maintenance</li> </ul> <p> </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 style="margin-bottom:12px"><strong>Self-Funded or externally sponsored students are welcome to apply.</strong></p> <p><strong>UK</strong> – The <a href="https://phd.leeds.ac.uk/funding/209-leeds-doctoral-scholarships-2022">Leeds Doctoral Scholarships</a> and <a href="https://phd.leeds.ac.uk/funding/234-leeds-opportunity-research-scholarship-2022">Leeds Opportunity Research Scholarship</a> are available to UK applicants. <a href="https://phd.leeds.ac.uk/funding/60-alumni-bursary">Alumni Bursary</a> is available to graduates of the University of Leeds.</p> <p><strong>Non-UK</strong> –The <a href="https://phd.leeds.ac.uk/funding/48-china-scholarship-council-university-of-leeds-scholarships-2021">China Scholarship Council - University of Leeds Scholarship</a> is available to nationals of China. The <a href="https://phd.leeds.ac.uk/funding/73-leeds-marshall-scholarship">Leeds Marshall Scholarship</a> is available to support US citizens. <a href="https://phd.leeds.ac.uk/funding/60-alumni-bursary">Alumni Bursary</a> is available to graduates of the University of Leeds.</p> <p><strong>Important: </strong> Any costs associated with your arrival at the University of Leeds to start your PhD including flights, immigration health surcharge/medical insurance and Visa costs are <strong>not</strong> covered under these studentships.</p> <p>Please refer to the <a href="https://www.ukcisa.org.uk/">UKCISA</a> website for information regarding Fee Status for Non-UK Nationals.</p>

<p>For further information about  your application, please contact Doctoral College Admissions: e: <a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions</a><a href="mailto:EMAIL@leeds.ac.uk">@leeds.ac.uk</a></p> <p>For further information rabout this project, please contact Professor Dejian Zhou by email:  <a href="mailto:D.Zhou@leeds.ac.uk">D.Zhou@leeds.ac.uk</a></p>