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The Diagnostics and Surveillance theme of the CDT will focus on the development and testing of rapid diagnostic tests, digital health and improved surveillance systems
Early detection and diagnosis of AMR is critical to antimicrobial stewardship, public-health surveillance and to prevent transmission. However, there remain many critical engineering challenges. For example, to determine antimicrobial resistance and susceptibility, current “gold-standard” methods often rely on bacterial culture in centralised laboratories requiring 36- to 72-hour turnaround times after sample collection. This is too slow for effective antibiotic stewardship in emergency settings or during short clinic visits. Lateral flow tests are emerging as an important tool for public health, but many lack the sensitivity to detect early-stage infections, as well as the digital connectivity to link data into healthcare systems. Moreover, relatively little is known about the interconnectedness of AMR in animals and the environment (e.g., wastewater), since most AMR studies focus on cases in humans based on electronic patient records in hospitals.
There is an urgent need for new engineering solutions to tackle these challenges. These should cover the generation of rapid ultra-sensitive tests to detect AMR in a variety of decentralised settings (e.g.,GP surgeries, care homes, self-testing in the home, point-of-pen and wastewater surveillance), and also the need for improved surveillance of outbreaks bringing together siloed data sets between humans, animals and the environment using a One Health approach.
Research Theme Contacts:
Prof. Rachel McKendry & Dr. Mike Thomas
2025 Projects
- Developing Amplification Strategies for Ultrasensitive and Rapid Antimicrobial Susceptibility Testing
Supervisors
Project Details:
Antimicrobial susceptibility testing (AST) is key to effective antimicrobial stewardship. Typically, it relies on bacterial culture, which can take as long as 1-7 days hindering time to results in urgent situations. New diagnostic assays aim to detect bacterial infections earlier and in a cost-effective way, focusing on either molecular testing for resistance genes or by binding bacteria-specific proteins. Recent examples include lateral flow assay (LFA) tests targeting the enzymatic machinery responsible for resistance, offering high sensitivity and specificity in identifying resistance from 18-24h bacterial cultures.1 However, faster methods for easier antimicrobial stewardship are needed. Here we will design new routes to enable chemical amplification to increase the sensitivity of rapid, cheap LFAs for AST, and reduce the need for culture.
We will focus on scaling down the bioassays in a rapid test format to minimise amounts of antibiotics needed for AST and bacterial load needed for detection. The research will leverage model bacterial platforms such as E.coli with a resistance gene inserted, or absent. Such a model system, common for transformation studies will allow the student to probe for the resistance machinery of the bacteria. Reagents capable of responding specifically to this machinery will be designed and produced, and the resulting assays evaluated/optimised against CFU/mL limits of detection. We have recently developed computational models of similar immunoassays employed in various formats and have a breadth of experience in lateral flow assay development.2-6 In particular we have expertise in LFAs that are responsive to chemical transformations that enhance sensitivity positioning us well to tackle this exciting approach to advancing rapid AST.
This interdisciplinary project will develop expertise in synthetic biology, bacterial culture, protein engineering, immunoassay development, and lateral flow assay device engineering. The student will also learn standard analytical techniques like SDS-PAGE, chromatography, ELISA, and have opportunities to apply automated liquid handling and simulation (Matlab) skills to support applying digital twin simulations developed in the Thomas Lab. The student can also expect to develop excellent spoken and written communication skills via publication, and attendance at leading international conferences.
Students in the Thomas and Frank labs at UCL benefit from a nurturing environment with significant hands-on time with supervisors during weekly and group meetings. PhD students receive close monitoring and support, especially towards their thesis and publications. Students can develop broader skills by attending various courses on research skills, data science, biomanufacturing, and more, ensuring their molecular biology skills are industry ready as well. The project also benefits from access to extensive facilities in the Dept Biochemical Engineering and the Bionano laboratory at the London Centre for Nanotechnology. The student will integrate into the diverse and supportive communities of both labs, where an emphasis on EDI, student welfare, and professional development is integral to our approach.
1) Hazim et al. The Journal of Molecular Diagnostics, 22(9), 1129 (2020)
2) Loynachan et al. ACS Nano 2018, 12, 1, 279.
3) Budd, J et al. Nat Rev Bioeng 1, 13-31 (2023)
4) Richards, D et al. Nanoscale, 13, 11921 (2021)
5) Miller, BS et al. Biosensors & Bioelectronics, 207, 114133 (2022).
6) Ayrton, JP et al. Nanoscale,16, 19881 (2024).
- Multiplexed lateral flow assay devices for early diagnosis of urinary tract infections in the community.
Supervisors
Project Details:
Urinary Tract Infections (UTIs) are among the most common infectious diseases worldwide. In primary care settings, UTIs are typically diagnosed via dipstick testing, which may lead to empirical antibiotic prescriptions. However, dipstick tests cannot identify specific pathogens, and the use of broad-spectrum antibiotics may favour the development of multidrug-resistant organisms. Current lateral flow assay (LFA) technologies are inadequate for UTI diagnostics in community settings due to their limited accuracy.
This project aims to develop a novel LFA device for UTI diagnostics in primary care settings that combines the rapid, point-of-care analysis of dipsticks with the accuracy and breadth of diagnostic information provided by traditional, time-consuming laboratory techniques. To deliver this technological breakthrough, a novel enzyme-free DNA amplification strategy will be combined with a power-free electrokinetic amplification strategy in a LFA testing format.
The project objectives are
- Design and optimise new enzyme-free DNA amplification strategy [1] that, upon interaction with a DNA/RNA target, rapidly release many labelled compounds.
- Design and optimise a LFA device that accumulates the released labelled products at the test lines by electrokinetic effects [2].
- Validate a colorimetric LFA prototype for rapid and ultrasensitive quantitative multiplexed detection of UTI pathogens and antibiotic resistance biomarkers.
Such an innovative LFA device could support the NHS by enabling rapid, affordable and widely accessible early diagnosis of infectious diseases, reducing morbidity and mortality rates, lowering healthcare costs, and enhancing the detection of AMR in the community.
To deliver the project objectives, the student will develop fundamental knowledge across multiple disciplines (e.g. DNA nanotechnology, colloid and interface science, microfluidics) and they will acquire interdisciplinary technical skills, including (i) nucleic acid design and analysis, (ii) characterisation of liquid and particle dynamics, (iii) design, fabrication and evaluation of lateral flow testing devices. The student will adopt a broad range of experimental techniques (gel electrophoresis, electron/optical microscopy, light scattering, laser manufacturing, spectroscopy and digital image analysis) and they will also acquire key programming skills for data analysis.
The student will join Dr Bolognesi’s Particle Microfluidics Group and the Booth Research Group and will also engage in collaborations with the network of academic and industrial collaborators of Dr Bolognesi and Dr Booth in the UK and overseas.
References
[1] G. Xu, M. Lai, R. Wilson, A. Glidle, J. Reboud and J.M. Cooper, Branched hybridization chain reaction—using highly dimensional DNA nanostructures for label-free, reagent-less, multiplexed molecular diagnostics. Microsystems & Nanoengineering, 2019, 5, 37.
[2] A. Chakra, N. Singh, G.T. Vladisavljevic, F. Nadal, C. Cottin-Bizonne, C. Pirat and G. Bolognesi. Continuous manipulation and characterization of colloidal beads and liposomes via diffusiophoresis in single-and double-junction microchannels. ACS Nano 2020, 17, 14644-14657.
- BEDside Levels of Antibiotic Monitoring (BEDLAM).
Supervisors
Project Details:
Rationale and background: Infection can lead to organ dysfunction (sepsis) which causes 20% of global deaths. The treatment mainstay is antibiotics however, increasing antimicrobial resistance (AMR) and lack of new options mandate better stewardship and better use of existing drugs. Antibiotic prescriptions are based on a one-dose-fits-all strategy with arbitrary dose reductions in those with severe liver and/or renal dysfunction. Blood levels of the commonest antibiotic class (ß-lactams) are not routinely measured by hospital labs. However, studies show suboptimal or excessive blood levels in significant numbers of intensive care patients due to altered drug metabolism. This increases the risk of (i) under-treating the infection resulting in death and an increased likelihood of inducing AMR; and (ii) side-effects from over-dosing.
Aims and objectives: We aim to develop a bedside monitor to measure ß-lactam blood levels within minutes, allowing rapid titration of drug dosing to optimal effect. In our pilot study underpinning this project, we can accurately (using LC-MS as a gold standard comparator) measure the ß-lactam antibiotic, meropenem within 10 min in spiked blood samples using aptamer technology. This utilises their high affinity and tunable properties, with sensitivity greatly influenced by the transducer. We wish to develop this further using conductive polymers (widely used in biosensor development) that can be processed at scale at low cost.
The CDT student will further develop our impedance biosensor by optimising geometry of the sensing electrodes, materials and chemistry, creating readout electronics and algorithms to analyse biosensor readings, in collaboration with our clinical partners. The student will acquire skills in these multi-disciplinary research domains. Intellectual property will be sought on use of novel polymers, biosensor construction and readout electronics. We will explore ß-lactam measurement in body fluids and tissues to assess antibiotic levels in organs from septic and healthy animals. This is readily achievable in our well-established lab models, and the successful student will have the opportunity, if desired, to develop physiological and biological skills.
Project plan:
- Obtain blood from critically ill patients and conduct a large study to test sensitivity and specificity of the novel biosensor [Y3]
- Develop sensor readout electronics and processing algorithms [Y2-Y3]
- Extend ethical permission to undertake early patient sample evaluations [Y2]
- Investigate performance using volunteer blood/plasma spiked with meropenem. Ethics in place [Y1-Y2]
- Develop biosensor coupling chemistry to detect antibiotic levels [Y1]
- Assess antibiotic levels in organ beds in laboratory models [Y4]
References:
- Hospital Wastewater Metagenomic Sequencing for Single Test Antimicrobial Resistance Surveillance and Monitoring
Supervisors
Project Details:
The Magic Wands Study which employs metagenomic sequencing to understand antimicrobial resistance in hospital wastewater has already been launched in Peru (Figure 1). The successful applicant to this project will have an opportunity to visit Peru and learn the metagenomic techniques necessary to be able to apply this at a UK hospital for drug resistance testing and novel pathogen discovery.
Rationale and Background: Implemented over the last decade by both supervisors, Great Ormond Street Hospital’s (GOSH) advanced Antimicrobial Resistance (AMR) surveillance systems screen every patient for pathogens resistant to last line therapies. Automated reporting using a customized electronic patient record allows staff to select alternative prophylaxis or treatments based on live AMR data. However, hospital wide surveillance of AMR is costly, labour intensive and time consuming. In a single test, wastewater metagenomic surveillance has the potential to cost-effectively evaluate hospital level AMR and simultaneously detect hospital outbreaks.
Aims and Objectives: This project will deploy hospital level wastewater metagenomic sequencing as a screening test for AMR in healthcare facilities. The following outcomes will be delivered:
1) Define the performance of hospital wastewater metagenomic sequencing for detecting resistance prevalence and mechanisms of hospital-wide AMR.
2) Maximise the sensitivity of sequencing using bait capture sets for a wide range of target pathogens.
3) Amplify whole genomes from target organisms using custom made primers to characterise AMR at pathogen level.
Methods and Groundwork: The MAGIC-WANDS study:
This study - led by UCL based PI Professor Louis Grandjean supported by funding from the Wellcome Trust - already undertakes monthly hospital wastewater sequencing in Peru using the latest Oxford Nanopore (ONT) to develop pipelines that enable reliable and quantifiable detection of the most dangerous hospital acquired drug resistant infections. In parallel we will undertake whole genomic sequencing of gram-negative isolates from hospitalized inpatients screened as part of GOSH's existing AMR screening program. The Centre for the Evaluation and Treatment of Resistant Infection (CENTRI):
CENTRI, led by lead supervisors (Grandjean and Hatcher) at GOSH, has well established pipelines for high throughput DNA extraction and sample processing using the automated Hamilton Star. Long standing collaboration with Yale University will enable us to evaluate custom made bait capture sets and genome spanning primers to detect and characterise organisms of interest.
Skills Development and Student Experience: The student that receives this funding award will join a dynamic and friendly team that will enable them to build skills and experience in epidemiology, field work, microbiology, molecular biology, bioinformatics, data-analysis, grant and manuscript preparation. The student will also be supported to visit our laboratory in Peru where we have implemented many of these techniques already and to learn from the laboratory team there.
Impact: This proposal will combine state-of-the-art AMR reporting at GOSH together with the latest in wastewater genomic technology to enable sensitive, reproducible surveillance and quantification of AMR at the hospital level.
- Developing optical methods to detect and isolate antimicrobial persisters
Supervisors
Project Details:
Antimicrobial resistance (AMR)—widely seen as the greatest challenge facing modern medicine—is projected to cause 10 million deaths annually by 2050 [1,2]. Already, bacterial infections are responsible for at least one in eight deaths globally [2]. The phenomenon of antimicrobial persistence, where bacterial populations survive antibiotics without genetic resistance, is even more pervasive than AMR, but remains highly enigmatic.
Persistence involves a small subset of bacterial cells that temporarily halt growth, which allows them to survive antibiotic treatment and potentially later resume growth, causing recurrent and chronic infections [3,4]. The current gold standard for diagnosing persistence is the biphasic killing curve (see figure), which is based on colonies counted on plates after a period of incubation. However, this method is exceptionally slow, which hampers timely clinical decision-making. Understanding the nature of these cells is limited by our inability to isolate them. This PhD project aims to revolutionise the detection and understanding of bacterial persistence through advanced fluorescence imaging and cell-sorting techniques. The student will first map the metabolic state of non-growing cells using fluorescence imaging. Next, optical proxies for persistence will be applied in the development of protocols for isolating persisters using fluorescence-activated cell sorting (FACS). This will then allow insights into the nature of the persister phenotype to be obtained and methods to inhibit the resumption of growth to be explored, ultimately allowing the identification of treatments aimed at preventing recurrent infections.
This project offers a unique chance to undertake cutting-edge research with significant implications for global health. Students participating in this project will gain a comprehensive interdisciplinary skill set, including technical skills in bacterial cell culture, advanced fluorescence imaging techniques and data analysis, proficiency in using fluorescent probes to assess cellular metabolic states, and expertise in FACS for isolating specific cell populations. The student will develop an in-depth understanding of bacterial persistence and antimicrobial resistance mechanisms, and experience in experimental design, data interpretation, and scientific communication. The focus of the McClelland group is experimental and quantitative microbiology, while the Blacker group develops quantitative fluorescence techniques for probing metabolism [5]. As a member of both research teams, the prospective student will be a member of an intellectually diverse, thriving research community, housed within the department of Structural and Molecular Biology at UCL.
This project is ideal for physical science graduates or highly quantitative biologists, with a knack for problem-solving. We welcome enthusiastic students who are eager to dive into microbiology, biochemistry, and experimental research. No prior experience in these fields is necessary—just a passion for learning and a drive to make a difference. For an informal discussion about the project, or to apply directly for this exciting opportunity, please contact Harry McClelland or Thomas Blacker.
References
[1] Naghavi, M. et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. The Lancet S0140673624018671 (2024) doi:10.1016/S0140-6736(24)01867-1.
[2] Murray, C. J. L. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 399, 629–655 (2022).
[3] Bigger, J. (1944). Treatment of Staphyloeoeeal Infections with Penicillin by Intermittent Sterilisation. Lancet, 244, 497-500.
[4] Balaban, N. Q. et al. Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 441–448 (2019).
[5] Blacker, T. S., Mann, Z. F., Gale, J. E., Ziegler, M., Bain, A. J., Szabadkai, G., & Duchen, M. R. (2014). Separating NADH and NADPH fluorescence in live cells and tissues using FLIM. Nature Communications, 5(1), 3936.