Biological Sciences

Mechanism of action of antimicrobial peptides

Supervisors

Jane Allison
Alan Cameron
Paul Harris

Discipline

School of Biological Sciences

Project code: SCI001

Project

Antimicrobial resistance is increasing worldwide, making the development of new antimicrobial agents is critical to fighting infection. Antimicrobial peptides (AMPs) function primarily by targeting the cell membrane, with selectivity for pathogens based on differences in the membrane lipid composition. However, AMPs are expensive to make, vulnerable to digestion, and not always great at getting to the site of infection. We use molecular dynamics computer simulations to understand how AMPs work and to explain why some are more effective than others.

What you will do: This project involves using computer simulations to investigate how AMPs interact with bacterial cell membranes, and interpreting this data to rationalise experimental results and help design effective AMPs.

What makes a successful applicant: A background in chemistry, biochemistry or structural biology is ideal. Some basic programming skills would be useful, but not essential. We will teach you how to set up and run the computer simulations, so all you really need is enthusiasm and a willingness to learn!

Preventing biomedical devices from stimulating blood clotting

Supervisors

Jane Allison
Chiara Neto (The University of Sydney)

Discipline

School of Biological Sciences

Project code: SCI002

Project

The surfaces of implanted biomedical devices can cause blood clotting. Blood clotting is activated by adsorption of proteins such as Factor XII to the surface of the device. Ultimately, fibrinogen, platelets and cells attach to form a complete blood clot. This can prevent the device from functioning properly and can cause thrombosis. Biologically-inspired Teflon-like surfaces reduce clotting, but liquid-infused surface coatings (LIS) have been shown to significantly prevent the build-up of blood clots. However, the exact mechanism by which they work is not understood.

What you will do: This project involves using computer simulations to study how blood clotting proteins interact with oil/blood interfaces, and using the results to understand why liquid-infused surfaces are anti-thrombotic and to improve their design.

What makes a successful applicant: A background in chemistry, biochemistry or structural biology is ideal. Some basic programming skills would be useful, but not essential. We will teach you how to set up and run the computer simulations, so all you really need is enthusiasm and a willingness to learn!

Insect diversity on Rangitāhua

Supervisors

Jacqueline Beggs

Peter Bellingham

Discipline

School of Biological Sciences

Project code: SCI003

Project

In 2002, feral cats and rats were eradicated on Raoul Island, 1000km northeast of Auckland. This is the largest island in the Kermadec Island Nature Reserve - an internationally significant chain of oceanic islands formed by volcanic action. As part of a larger programme of research (Te Mana o Rangitāhua) led by Ngāti Kuri and Auckland Museum, this project will assess the impact of removing introduced cats and rats on the invertebrate fauna. You will document and measure Rangitāhua specimens in museum collections, comparing the diversity and morphology of insects prior to predator eradication with post-eradication specimens. Depending on the timing of voyages to Rangitāhua and the collection of new material, there may be the opportunity to work with freshly collected specimens. We predict there will be an increase in size class in the absence of introduced predators. You will develop a range of entomological skills, particularly in relation to morphological measurements, species identification, data management and statistical analyses. We prefer a candidate with a passion for ecology and New Zealand’s biodiversity and a willingness to engage with iwi to communicate results. There is potentially scope to develop this work into postgraduate research.

Variation in myrtle rust susceptibility of pōhutukawa in Auckland city

Supervisors

Associate Professor Bruce Burns
Dr Maj Padamsee

Discipline

School of Biological Sciences

Project code: SCI004

Project

Myrtle rust (Austropuccinia psidii) is a virulent plant pathogen of the family Myrtaceae, with the rust now having spread globally and infecting >500 plant species. It arrived in New Zealand in 2017 and is still spreading. Because it is a recent arrival, our understanding of host susceptibility is also still developing, both within and amongst species. For pōhutukawa within Auckland, infections of individuals seem to vary by location, plant size, proximity to roads, and whether the plant was planted or wild grown. Sometimes infected plants and healthy plants occur in close proximity. This proposed project would survey pōhutukawa within Auckland for infection status and a range of potential factors (e.g., size, proximity to roads, and likely origin) that may describe susceptibility to infection. These data would then be analysed for infection patterns. The goal would be to determine correlative evidence for factors that might facilitate myrtle rust infection to better understand the infection process.

Alternative hosts of Phytophthora cinnamomi and P. agathidicida in a local kauri forest

Supervisors

Bruce Burns

Nari Williams

Shannon Hunter (PhD student)

Discipline

School of Biological Sciences

Project code: SCI005

Project

Kauri (Agathis australis) forests are under threat by the pathogen Phytophthora agathidicida which causes kauri dieback. Both P. agathidicida and P. cinnamomi are frequently isolated from kauri soil samples. Phytophthora cinnamomi has the largest known host range of all Phytophthora species globally, so it of interest to determine if P. cinnamomi (or P. agathidicida) can be found infecting the roots of common native plants in a local kauri forest. The student will determine which host plants to include, plan the experimental design for sampling, collect soil samples (field work), isolate Phytophthora cultures and identify them morphologically.

Prerequisite course: BIOSCI 324

Miromiro/tomtit song rates across breeding stage: testing for sexual and nonsexual functions of song

Supervisor

Kristal Cain

Discipline

School of Biological Sciences

Project code: SCI006

miromiro / tomtits

Project

This study will examine song rates in both sexes across the breeding season to determine whether song is more important for sexual (mate attraction, fertility advertisement) or nonsexual (territorial defence, pair-bond maintenance) in the common, but poorly studied miromiro/tomtit.
The project will focus on the Hunua Ranges population.
We will also be catching and banding individuals and searching for nests.
Requirements: No particular experience or skills needed but enthusiasm and willingness to learn a must. Due to the location of the field site, having access to a car is essential.

The cell-type specific roles of mitochondria and chloroplasts in plant cells.

Supervisor

Chris Carrie

Discipline

School of Biological Sciences

Project code: SCI007

Project

Mitochondria and chloroplasts are essential for plant cell metabolism. Providing not only energy and carbon sources but they have evolved to also play vital roles in amino acid metabolism, hormone biosynthesis and cellular signalling. We have recently developed a new method for isolating either mitochondria or chloroplasts in a cell-type specific manner. Allowing for the first time the cell-type specific roles of mitochondria and chloroplasts to be studied in detail. This project will harness these new techniques to examine the roles of these organelles in the different cell-types of roots. Project would suit someone with a strong molecular biology background interested in plant biology.

Assessing the distribution and drivers of phytoplankton abundance in the Southwest Pacific

Supervisor

Dr. Alice Della Penna (IMS+SBS)
Prof. Mary Sewell (SBS)
Dr. Denise Fernandez (NIWA)
Dr. Joe O’Callaghan (NIWA)

Discipline

School of Biological Sciences

Project code: SCI008

Project

Understanding how phytoplankton distribution changes in time is crucial to evaluate their impact on the global carbon cycle. This project consists in a set of analyses of observations already collected by Bio-Argo floats (robots that sample the ocean autonomously; https://fleetmonitoring.euro-argo.eu/).

The goal is to understand the temporal variability of phytoplankton and nitrates as well as physical and chemical properties such as temperature, salinity, and oxygen concentrations.

Ideal student: This project is ideal for a student who is interested in physical/biological interactions in the ocean, has a background in oceanography (physical or biological) or marine ecology and has experience with the analysis of oceanographic data in MATLAB or Python (or have an interest in learning)

This project is in collaboration with NIWA with possibilities for the student to be based in Auckland or Wellington.

Exploring seabird colour and vision using sensory ecology

Supervisor

Ariel-Micaiah Heswall (Ph D student)
Dr. Anne Gaskett

Discipline

School of Biological Sciences

Project code: SCI009

penguins

Project

“Peering through the eyes of a seabird”
Aotearoa is a diverse seabird hotspot with over a quarter of the world’s seabird species! To our eyes seabirds are usually monotonous in colour, however, a serendipitous finding has shown that seabirds maybe more colourful than once thought…
Also, it is theorized that some seabirds can see UV but recent findings show that might not be the case for some species…
This exciting research project will involve a mixture of lab work, computer work and live observations of seabirds (including working with penguins) at various locations such as at the Auckland Museum, Kelly Tarltons, Grafton lab and BirdCare Aotearoa.
Would you like to be a part of the seabird project that explores the world through a seabird’s eyes and questions mainstream ideas and assumptions regarding seabird colour and perception? If so then this is the right project for you and we look forward to welcoming you onboard!

Modelling the rate of language change

Supervisor

Simon J. Greenhill

Discipline

School of Biological Sciences

Project code: SCI010

Project

Languages evolve over time just like species do but there is massive variation in just how fast languages evolve: some languages are highly stable over hundreds of years, while others have radically reorganised themselves.

This project will use phylogenetic methods to infer and quantify the rates of language evolution across the world’s major languages families. Which languages are evolving the fastest and which are the most stable over time, and how might we explain this variation?

Requirements: Applicants for this project should have some background knowledge of computational phylogenetic methods and an interest in languages.

Flattening the curve (the steep R learning curve)

Supervisor

Charlotte Jones-Todd

Disciplines

Biological Sciences and Statisics

Project code: SCI011

Project

Remember the first time you learnt R: error messages aplenty and missing brackets in their droves. Now you’ve got a handle on R, it’s your turn to mould the learning journey for future newbies.

This project will extend an R-based interface that exposes new users to common R errors and encourages them to problem solve to find the solution. This will be specifically targeted to biostatistics students who often have not been exposed to R or any other programming language. Upon completion the interface will eventually be integrated into BIOSCI220.

Strong R programming skills would be an advantage.

Developing antiviral compounds capable of targeting human respiratory viruses

Supervisor

Dr Richard Kingston

Discipline

School of Biological Sciences

Project code: SCI012

Project

Respiratory viruses place hundreds of New Zealanders in hospital each year, and cause life threatening illness in the young, the old, and those with weakened immunity. Our lab is helping develop antiviral compounds that could act against these viral pathogens by shutting down their ability to synthesize nucleic acids - a process absolutely central to the propagation of infection.

In this project you will work as part of a team, helping to purify viral RNA polymerases; assess the effects of antiviral nucleoside analogs on polymerase activity; and perform structural analysis of drug-polymerase complexes in order to understand the mechanism of action.

Requirements: The project is suitable for someone with a background in protein science, and an interest in protein structure, enzyme catalyzed reactions, and antiviral drug design.

Searching for new antibiotics

Supervisor

A/Prof Shaun Lott

xtn 87074

Discipline

School of Biological Sciences

Project code: SCI013

Project

Antibiotics are a special category of drug that underpin modern medicine as we know it. Resistance to antibiotics is a growing global problem, which is estimated will place 10 million lives per year at risk by 2050 without action. This project will focus on understanding enzymes that are potential targets for new antibiotics.

Ideal student: This project is best suited to someone with a strong interest in protein structure and function and/or microbiology.

Improving enzymes for plastic degradation

Supervisor

A/Prof Shaun Lott

xtn 87074

Discipline

School of Biological Sciences

Project code: SCI014

Project

Plastic waste is a world-wide problem. In New Zealand, more than 25,000 kg of plastic waste is discarded every day and only 7% of PET (polyethylene terephthalate ♳) plastic waste is fully recycled. This project will focus on engineering a more effective way to break PET down into its environmentally benign components, terephthatlic acid (TPA) and ethylene glycol (EG), by linking thermostable enzymes onto a novel, patented bio-scaffold. This will bring plastic waste into the circular economy - ōhanga āmiomio.

Ideal student: This project is best suited to someone with a strong interest in the structure and engineering of proteins.

Investigating premature cardiovascular disease burden for Aotearoa-based descendants of indentured labourers

Supervisors

Dr Pritika Narayan

Dr Gisela Kristono

Discipline

School of Biological Sciences

Project code: SCI015

Project

Premature cardiovascular disease (CVD) is known to have a genetic basis linked with ancestry, however evidence for this is significantly lacking for ethnic minority groups living in Aotearoa. Fijian Indians (of whom a vast majority descend from Indentured labourers trafficked to Fiji between 1879 and 1920) form almost 2% of Aotearoa’s population. However due to incorrect ethnicity capture, the true disease burden is not accurately reported. This summer studentship will statistically analyse national data sets obtained from Ministry of Health on CVD mortality using relevant codes from the Mortality Collection Data Set (MORT), and ICD-9-CM-A and ICD-10-AM, and CVD hospitalisations using relevant codes from the National Minimum Data Set (NMDS), and the ICD-9-CM-A and ICD-10-AM for the last 25 years (i.e.1996-2021), with additional data dimensions of birthplace, language spoken, age and sex. This studentship will investigate differences in CVD mortality and hospitalisations between for example, Indians born in Fiji versus Indians born elsewhere, or Fijians who are Fiji-Hindi speakers versus other language speakers; to demonstrate whether these additional dimensions can provide surrogate estimates for disease burden among descendants of Indentured labourers from Fiji.

Requirement: Must have a strong interest in the health outcomes of minority ethnic groups such as Fijian Indians.

Timeframe: This project is expected to take 10 weeks

Illustrated guide - Rimurimu (seaweeds) of Rangitāhua

Supervisor

Wendy Nelson

Discipline

School of Biological Sciences

Project code: SCI016

Seaweed

Project

Rangitāhua (Kermadec Islands) is the most northern part of the NZ archipelago and home to many tropical and subtropical seaweeds not found on mainland NZ. This project involves compiling underwater photographs, imaging herbarium specimens, and assembling information about species for an identification guide that is being built up over the course of the Te Mana o Rangitāhua research programme.
This project will be based in Wellington at NIWA and will involve photography of specimens, building up databases of images and species information, and learning about these intriguing algae.

Effects of leaf expansion traits on myrtle rust susceptibility

Supervisors

Dr Maj Padamsee
Associate Professor Bruce Burns

Discipline

School of Biological Sciences

Project code: SCI017

Project

Myrtle rust (Austropuccinia psidii) is a virulent plant pathogen of the family Myrtaceae, with the rust now having spread globally and infecting >500 plant species. It arrived in New Zealand in 2017 and is still spreading. Susceptibility to myrtle rust is highly variable amongst species and it is not clear what plant traits facilitate infection. Myrtle rust infections are usually initiated on the newly expanding and soft tissue of leaves, flowers, or stems, but differences in traits associated with these processes of expansion and hardening off amongst species are not documented. This project would stringently follow leaf expansion processes on a number of Myrtaceae species over time and record traits relevant to infection susceptibility, e.g., leaf SLA, cuticle development, phenology, etc. Relating these traits against known infection susceptibilities may lead to greater understanding of variation in infection susceptibility.

Molecular analysis of gene-edited plants

Supervisor

Prof Jo Putterill

Discipline

School of Biological Sciences

Project code: SCI018

Project

Flowering time is an important trait for plants and crops because it affects plant productivity and yield. Legumes are the second most important group of crop plants after the cereals. Plants control flowering time differently so each group of plants requires analysis. Thus we study flowering time control in the model legume, Medicago and in kiwifruit (with Plant and Food Research). We are using gene editing to knock out candidate flowering time control genes.
Skill development: You will learn plant molecular biology techniques including how to make gene editing constructs, designing primers, transformation of bacteria and plants and PCR. You will learn how to keep a research lab book, trouble shoot experiments and write up the project report.
Skills required: Skills in molecular biology and genetics with an interest in plant development. BioSci papers such as 202, 351, 355 and 326 provide good background.
Personal attributes: A sense of curiosity. You need to be able to work both as part of a friendly team and independently. To be punctual, work hard and stay focused with strong attention to detail.

Motor neuron disease: Why motor neurons?

Supervisors

Emma Scotter
Molly Swanson
Maize Cao

Discipline

School of Biological Sciences

Project code: SCI019

Project

Motor neuron disease is a fatal and incurable movement disorder affecting ~1 in 15,000 New Zealanders. Most people with motor neuron disease harbour aggregates (clumps) of the protein TDP-43 in the motor neurons that degenerate. Other cell types such as oligodendrocytes, astrocytes, and microglia harbour occasional TDP-43 aggregates but certainly less frequently than do neurons. This project aims to use publicly available single cell data to compare the RNA expression of TDP-43 between human brain cell types, and correlate these findings to immunostaining of TDP-43 protein in human brain. The RNA expression of TDP-43 interactors and proteins that degrade TDP-43 will also be examined. If the burden of TDP-43 aggregates in different cell types relates to their RNA and protein load of TDP-43, and/or to the expression of TDP-43 degrading proteins, this would rationalise therapeutic approaches that reduce TDP-43 levels.

Techniques:
- Database analysis/ basic bioinformatics
- Multiplexed human brain immunohistochemistry
- Multiplexed tissue imaging
- Automated image analysis
- Scientific writing

The student will be based at the School of Biological Sciences, University of Auckland. This pilot project is part of a larger program of research and there is potential for a successful candidate to continue into a Masters or PhD project. The Scotter lab is a diverse and safe lab- we welcome applications from all students.

The coastal meroplankton of Rangitāhua (the Kermadecs)

Supervisor

Prof Mary A. Sewell

Discipline

School of Biological Sciences

Project code: SCI020

Project

Plankton samples that have been previously collected at different locations in Rangitāhua will be examined in the laboratory using a microscope, with a focus on quantifying the meroplankton (larval stages of marine invertebrates and fish). Photographic images of rare and abundant meroplankton will be used to start an identification guide for future research at Rangitāhua in a MBIE project (Te Mana o Rangitāhua) with Ngati Kuri and Auckland Museum.

Ideal student: An understanding of marine invertebrate diversity would be a distinct advantage (e.g., completion of BIOSCI 208 or similar Invertebrate Diversity course), but on-the-job training will be provided during the project. Ideally suited for a student with interests in biodiversity, identification of small organisms, and in gaining skills in scientific photography and illustration.

Use of lipids during larval development in echinoderms

Supervisor

Prof Mary A. Sewell

Discipline

School of Biological Sciences

Project code: SCI021

Project

The yolk of echinoderm eggs contains lipids, proteins and carbohydrates to provide the energy for larval development, with lipid shown to be the most important. Using an instrument that quantifies lipids (an Iatroscan) we will examine use of lipid during larval development from fertilized egg to early larvae in a local starfish (Stegnaster) and an Antarctic sea urchin (Sterechinus) using previously collected samples.

Ideal student: This project is ideally suited for a student with some background in biochemistry, an interest in larval development, and in developing laboratory skills in this area of research.

Multiple weed impacts and management

Supervisor

Assoc. Prof. Margaret Stanley

Discipline

School of Biological Sciences

Project code: SCI022

Project

Most weed research has been focused on single weed species. However, the impact of multiple weeds within one site can be complex and managers need research to determine whether weeds help or hinder each other – and to make decisions on the order of weed removal without having unintended consequences. This project will be aligned to an existing PhD project on multiple weed impacts in mānuka/kānuka ecosystems and will involve a combination of shadehouse experiments and fieldwork. There may be an opportunity to work with Māori growers in the Bay of Plenty as part of the Bioprotection Aotearoa Centre of Research Excellence’s focus on ecosystem restoration underpinning community wellbeing.

Requirement: Need own transport and driver’s licence. Opportunity to work within a larger, supportive research team.

Understanding peptide hormone effects to target obesity

Supervisors

Dr Christopher Walker

Dr Tayla Rees

Discipline

School of Biological Sciences

Project code: SCI023

Project

Several peptide hormones represent excellent targets for the treatment of obesity and metabolic disorders. These peptides activate G protein-coupled receptors (GPCR) at the surface of the cell leading to specific biological outcomes. This project will investigate the cellular consequences (intracellular signalling) of receptor activation by a peptide hormone using plate-based technologies (eg. Alphascreen, HTRF, Elisa) in cell culture models. Modern therapeutic concepts, including biased agonism, will be addressed.

Genomic dark matter: should we pay more attention to transposable elements in species of conservation concern?

Supervisors

Dr Annabel Whibley
Dr Anna Santure

Discipline

School of Biological Sciences

Project code: SCI024

Project

The repetitive content of genomes is often neglected when studying adaptive potential but transposable elements could make major contributions to mutational load and fitness differences within lineages and between individuals. This project will apply a repeat annotation pipeline we have implemented in the lab on a broader taxonomic scale in order to explore transposable element landscapes in published reference genomes across a range of taxa of conservation concern and with a particular focus on Aotearoa New Zealand birds.

The project would involve comparative analysis of population parameters and genomic features of several species and would suit someone with an interest in bioinformatics, computational biology and/or data visualisation.

Success of Chinese privet biocontrol agents

Supervisors

Assoc. Prof. Margaret Stanley
Dr Imogen Bassett (Auckland Council)

Discipline

School of Biological Sciences and Auckland Council

Project code: SCI025

Project

This project assesses the establishment success and effectiveness of a weed biocontrol agent (lacebug) targeted at Chinese privet, a major environmental weed in Auckland (Ligustrum sinense).

Once non-target risks are assessed and permission given by EPA to release biocontrol agents, there is often very little monitoring of the fate of biocontrol agents. This project will involve surveying release sites for lace bug establishment and assessing damage to Chinese privet seedlings.

Requirements and benefits: Need own transport and driver’s licence. Opportunity to work with Auckland Council’s Biosecurity team.

Biodiversity of insects in a taxonomic collection at Landcare Research

Supervisors

Dr Darren Ward
Grace Hall
Dr Leanne Elder
Dr Aaron Harmer

Discipline

School of Biological Sciences and Manaaki Whenua - Landcare Research

Project code: SCI026

Project (Two students)

Work with taxonomists on the diversity of terrestrial insect species in New Zealand and the Pacific.

Learning research and technical skills to work in a taxonomic collection or natural science museum, including:

1) fieldwork and sorting field samples

2) curation and identification of insect groups

3) imaging specimens for machine learning / AI methods

4) Databasing and geo-referencing specimens for biodiversity and biosecurity research projects.

Requirements: Ability to work in a group or independently, position requires dexterity, care and attention to detail, data entry. Applicants should have an interest in Entomology, Taxonomy, Natural History.

All things Fungi: learning about mycology, plant pathology, and myrtle rust.

Supervisors

Mahajabeen Padamsee
Bevan Weir,
Peter Johnston

Discipline

School of Biological Sciences and Manaaki Whenua - Landcare Research

Project code: SCI027

Project

The Landcare Research fungal systematics group maintains the largest collections of both dried and living fungi in New Zealand, and delivers data associated with the collections through the NZFungi website. The successful applicants (X2) will provide assistance adding data to the fungal database, and maintaining, tracking, and storing fungal specimens and cultures and associated DNA sequence data. You will gain an understanding of the day to day running of a mycological research laboratory and key techniques you will learn include handling fungal cultures, data capture and management and microscopy. In addition, you will be expected to assist with an ongoing project on myrtle rust in the mycology labs at Manaaki Whenua-Landcare Research, Tamaki. These could potentially involve culturing and identification of fungi from field samples, analysis of DNA data, etc.

Requirements: Attention to detail, ability to keyboard accurately, a general interest in fungi, bacteriology or plant pathology.

Peptide Stapling to Selectively Target Biomolecules to Improve Therapeutic Performance

Supervisors

Dist. Prof. Margaret Brimble
Room 731B, 7th floor, building 301

Assoc. Prof. Paul Harris
Dr Alan Cameron
Phone: 09-9238259

Discipline

School of Chemical Sciences and School of Biological Sciences

Project code: SCI067

Project

Stapled peptides are an emerging class of therapeutics that bridge the gap between small molecule drugs and biologicals (e.g. monoclonal antibodies - Herceptin), allowing one to target protein-protein interactions (PPIs) once considered “undruggable”. Stapled α-helical peptides can mimic and block these crucial interactions occurring both within and on the surface of cells, covering larger binding surface areas than is typically possible with conventional small molecule drugs. As such, stapled peptides are expected to provide medicinal chemists access to countless new therapeutic targets in treatment of cancers, metabolic disorders (e.g. diabetes) and infectious disease (e.g. SARS-CoV-2).

Using modern organic synthesis techniques, linear peptides can be “stapled” to improve their α-helical secondary structure and biological activity properties. Stapled peptides benefit from enhanced receptor affinity and selectivity, improved membrane permeability (accessing intracellular targets) and increased half-lives in body.

The successful candidate will apply modern synthetic organic chemistry, developing new and improved stapling methodology to apply this towards medicinal targets which may include cancer treatments, combatting antibiotic resistance or anti-viral drugs.

Synthesis of New Generation Lipopeptide-based Antibiotics

Supervisors

Dist. Prof. Margaret Brimble
Room 731B, 7th floor, building 301

Assoc. Prof. Paul Harris
Dr Alan Cameron
Phone: 09-9238259

Discipline

School of Chemical Sciences and School of Biological Sciences

Project code: SCI068

Fig. 1 Kidney organoids left: healthy (untreated) centre: polymyxin treated right: analogue treated

Project

Antibiotic resistance has been recognised by the WHO as one of the greatest threats to humanity and infectious diseases rank as the second most common cause of death worldwide. New antibiotics are desperately needed!

Cyclic lipopeptides are an emerging subset of peptide-based antibiotics (e.g. daptomycin and polymyxin) containing a lipid or fatty acid. They have been shown to possess clinical efficacy and are used as the “last line of defence” against otherwise untreatable bacterial infections. Despite their promise, undesired toxicity is often a significant drawback of these antibiotics (e.g. polymyxin nephrotoxicity.

Our lab is developing novel, non-toxic derivatives of naturally occurring lipopeptide (Fig. 1) antibiotics by modifying the chemistry of the lipid tail and hydrophobic groups. The challenge remains, however, to efficiently produce new antibiotics based on a cyclic peptide scaffold incorporating the crucial lipid motif.

Using our “in-house” methods to install lipids onto peptides this project aims conduct an SAR study by generating a synthetic chemical library of analogues of natural lipopeptide antibiotics. Novel antibiotic analogues will undergo biological testing against multi-drug resistant (MRD) strains of bacteria and evaluation of potential toxicity to probe the SAR and establish their therapeutic potential.

Successful candidates will use organic synthesis techniques and modern methods of solid phase peptide synthesis. Candidates will also have the opportunity to undertake and learn biological assays if they desire.

Chemical Synthesis of a Conotoxin Derived from the Venom of Cone Snails

Supervisors

Dist. Prof. Margaret Brimble
Room 731B, 7th floor, building 301

Assoc. Prof. Paul Harris

Discipline

School of Chemical Sciences and School of Biological Sciences

Project code: SCI069

Project

Cone snails have evolved a venomous harpoon able to paralyse prey with an arsenal of toxic compounds, such as conotoxins, which show great promise in the treatment of conditions such as pain and neuromuscular disorders. κA-conotoxins are a major component of the venom of several species of fish-hunting cone snail, but as a class of compounds have been less well studied due to their molecular complexity and post-translational modifications.

CcTx is a 30 residue glycopeptide that contains an intricate serine-linked pentasaccharide, 3 intramolecular disulphide bonds, several hydroxylated proline residues and a C-terminal alpha helix spanning residues 23Ser-27Thr. The unique pentasaccharide moiety, which contains several rare and unnatural L-sugars, probably plays a key role in its bioactivity.

Using chemical synthesis techniques this project will embark on a total synthesis of CcTx using glycosylation and peptide chemistry to assemble the fully functional molecule from individual amino acids. Candidates will become well versed in modern methods of glycopeptide chemistry.

Natural Product Cytotoxic Payloads for Antibody–Drug Conjugates

Supervisors

Dist. Prof. Margaret Brimble
Room 731B, 7th floor, building 301

Assoc. Prof. Paul Harris
Dr Iman Kavianinia

Discipline

School of Chemical Sciences and School of Biological Sciences

Project code: SCI070

Project


Antibody-drug conjugates (ADCs) are a clinically proven class of medicines used in the treatment of various cancers. Utilisation of the exquisite selectivity of antibody targeting to cancer epitopes coupled to delivery of highly potent small molecules is revolutionising modern oncology. Given the modular nature of the ADC design concept, the future potential of this field is truly vast, and will rely on the discovery of i) new antibody-antigen couples, ii) novel linker chemistries and iii) the discovery of highly potent cytotoxins for conjugation.
Critically, the availability of suitably potent, stable cytotoxic agents is considered rate-limiting for progress in this field. Cytotoxic peptide natural products provide a rich source of anticancer agents that can be readily appended to antibodies using amino acid-based conjugation technology.
This research project provides a unique opportunity to develop a novel class of cytotoxin with optimal properties for use in ADCs. The student undertaking this project will be involved in modern solid-phase peptide synthesis, HPLC purification and compound characterisation using related spectroscopic techniques.

Linker Design for Antibody-Drug Conjugates

Supervisors

Dist. Prof. Margaret Brimble
Room 731B, 7th floor, building 301

Assoc. Prof. Paul Harris
Dr Iman Kavianinia

Discipline

School of Chemical Sciences and School of Biological Sciences

Project code: SCI071

Figure 1. General antibody-drug conjugates structure

Project

Antibody-drug conjugates (ADCs) are a clinically proven class of medicines used in the treatment of various cancers. The ADCs utilise monoclonal antibodies (mAbs) to specifically bind to the corresponding antigens present on the surface of cancer cells. This selective binding minimises the systemic toxicity associated with the anti-cancer treatment and significantly increases the pharmacological activity of the conjugated cytotoxin. The three main components of ADCs are the desirable monoclonal antibody, an appropriate linker and an active cytotoxic drug.

Linkers designed to be cleaved under specific cellular conditions include acid-labile hydrazone linkers sensitive to the low-pH conditions in the endosome and lysosome, disulfide-based linkers that can be reduced by the high (millimolar) levels of reduced glutathione in the cell cytosol compared to serum, or dipeptide linkers cleaved by specific lysosomal proteases. Despite considerable effort undertaken to design a stable linker between the antibody and cytotoxic agent, systemic toxicity is observed in several ADCs in clinical development. Therefore, interest in designing a suitable chemical linker that helps the antibody to deliver the cytotoxic agent specifically to cancer cell has become an important target for scientists involved in the development of novel antibody-drug conjugates.

The proposed research aims to generate a new class cleavable linkers that can facilitate efficient release of the cytotoxic agent at a targeted tumor site.

Natural Product Cyclic Depsipeptides as Antiviral Agents

Supervisors

Dist. Prof. Margaret Brimble
Room 731B, 7th floor, building 301

Assoc. Prof. Paul Harris
Dr Louise Stubbing
Dr Aimee Horsfall

Discipline

School of Chemical Sciences and School of Biological Sciences

Project code: SCI072

Project

Viral infections present a significant burden to public health worldwide, and despite extensive research there are numerous viral diseases without established direct treatment.
Two families of closely-related cyclic depsipeptides, the simplicilliumtides and verlamelins, have been isolated from the deep-sea fungus Simplicillium obclavatum EIODSF 020. Simplicilliumtide J and verlamelins A and B are hexapeptides that form a cyclic structure via an ester linkage between a 5-hydroxy fatty acid (highlighted in red) and a valine or allo-isoleucine residue. These cyclic depsipeptides displayed antiviral activity against the herpes simplex virus 1 (HSV-1, causative agent of most cold sores) in a plaque reduction assay, with IC50 values of 14.0, 16.7, and 15.6 µM, respectively.
This project aims to explore the structure-activity relationship of these cyclic depsipeptides in the context of antiviral activity. The student will undertake total synthesis of these natural products and rationally designed analogues, using both organic synthesis and peptide chemistry techniques.