A Cost-Effective High-Speed Clinical Diagnostics Instrument for Large Population Screening Based on Novel Liquid AP-MALDI MS Technology

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Based on previously funded EPSRC research (EP/L006227/1) for the 'Development of a novel MALDI mass spectrometer and technology for the generation of multiply charged ions at high sensitivity' and subsequent initial exploitation of this new technology, the proposed project will develop a new instrument that specifically fulfils key requirements in clinical diagnostics as demanded by modern medicine, in particular in the age of new pandemics such as COVID-19.Accurate and fast characterisation of microorganisms in clinical samples are crucial for initiating optimal treatment and limiting the outbreaks of pandemics. Both accuracy and time are key to the best treatment outcome for the patient, minimising the time to recovery and more importantly minimising morbidity and mortality. In particular, the correct and rapid identification of newly discovered microbial pathogens or antimicrobial-resistant strains is important for the patient's recovery. Combined with the capability of large-scale testing, it will also allow for a better global response to (microbial) infectious diseases.Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS) profiling of organisms (biotyping) has recently been established as a superior method to classical clinical microbiology assays for the identification of clinically relevant microbes with substantially increased classification accuracy and speed of analysis. This has already led to two FDA approved systems for microbial detection and identification by MALDI MS biotyping. In the proposed project, this methodology will be substantially advanced by exploiting multiply charged ions and their co-analysis with lipids and other biomolecules on a bench-top MS/MS instrument specifically optimised for large-scale, inexpensive clinical analyses, thus leading to the next generation of superior MALDI MS biotyping for clinical use and mass testing.The unique features of this new instrument and the associated technology will be high speed, cost-effectiveness, and high specificity by MS/MS sequencing. Combined with the unrivalled resolution of mass spectrometry this new technology will be a step-change in diagnostic testing by allowing the testing of multiple diseases within the same test run as well as being highly adaptable to new diseases without the need to develop test reagents that are disease/microbe-specific, difficult to source and therefore expensive, in particular for newly discovered diseases (cf. COVID 19). The aim is to reach a throughput level of 100,000 samples per day at high detection accuracy and low cost per sample.From collaborating with the biopharmaceutical industry and analytical instrument manufacturers, and from research of a BBSRC-funded grant, we found that our novel AP-MALDI MS ion source provides a sensitive platform for rapid assay analysis with the potential for use in the early detection of microbial diseases. The proposed project will build on this preliminary data, develop a new tailor-made instrument for future clinical use and explore the advantages (compared to current MALDI MS biotypers) in (a) speed, (b) the elimination of biological matrix background, (c) superior MS/MS analysis, (d) greater ion signal stability, (e) multiplexing capability and (f) the simpler (and cost-effective) but more flexible sample preparation that this new technology can offer.