RESEARCH
Staphylococcus aureus
We’re interested in understanding how S. aureus subverts macrophage function (particularly through regulation of toxin release by 2 component systems) and how the host innate immune system responds to infection.
Our work combines whole genome sequencing of both bacteria and host, forward and reverse genetic screening, advanced light microscopic techniques, and cellular and whole animal infection models to understand the molecular basis of bacteria-host interactions.
Related publications:
Innate Immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Hepburn L, […], Floto RA. Science. 2014 Oct 31;346(6209):641-6. doi: 10.1126/science.1258705. PMID: 25359976
Mycobacterium tuberculosis
We are interested in defining the critical molecular pathways that restrict intracellular bacterial growth. We are employing both CRISPR-Cas9 based forward genetic screens and candidate gene approaches from population genetic studies to identify key nodal genes and then understand their mechanism of action through cellular and biochemical analysis.
Related publications:
Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. Schiebler M, […], Floto RA. EMBO Mol Med. 2014 Dec 22;7(2):127-39. doi: 10.15252/emmm.201404137. PMID: 25535254
Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Floto RA, […], Smith KG, Lehner PJ. Science. 2006 Oct 20;314(5798):454-8. PMID: 17053144
Nontuberculous mycobacteria, (NTM)
We are focused on understanding the biology and pathophysiology of infection with the rapid growing multidrug resistant NTM Mycobacterium abscessus as part of the Cystic Fibrosis Trust Strategic Research Centre; an international collaboration with Professor Sir Tom Blundell (Biochemistry, Prof. Julian Parkhill (WT Sanger Institute), Drs Diane Ordway and Mary Jackson (Colorado State University). Together we combine population-level whole genome sequencing, cell biology, biochemistry, animal modelling, structural biology, and computational biology to reveal virulence mechanisms, define host defence factors, and develop novel antibiotics.
Related publications:
Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Bryant JM, […], Floto RA. Lancet. 2013 May 4;381(9877):1551-60. doi: 10.1016/S0140-6736(13)60632-7. PMID: 23541540
Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. Renna M, […], Floto RA. J Clin Invest. 2011 Sep;121(9):3554-63. doi: 10.1172/JCI46095. PMID: 21804191
Macrophage and Dendritic cell biology
We are working to understand how phagocytosis is regulated; how phagosomal pH, membrane integrity, and maturation is normally controlled and subverted by bacteria; and how autophagy may impact on intracellular bacteria survival.
We use novel fluorescent sensors and advanced microscopy (in collaboration with Dr Steve Lee, Chemistry Cambridge), model organisms such as dictyostelium (c/w Dr Rob Kay, MRC-LMB), and functional assays to understand the cellular regulation and molecular effectors of phagosomal function.
Related publications:
Innate Immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Hepburn L, […], Floto RA. Science. 2014 Oct 31;346(6209):641-6. doi: 10.1126/science.1258705. PMID: 25359976
Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. Schiebler M, […], Floto RA. EMBO Mol Med. 2014 Dec 22;7(2):127-39. doi: 10.15252/emmm.201404137. PMID: 25535254
Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. Renna M, […], Floto RA. J Clin Invest. 2011 Sep;121(9):3554-63. doi: 10.1172/JCI46095. PMID: 21804191
Cystic Fibrosis and Bronchiectasis
We are focused on improving the health of individuals with Cystic Fibrosis and related lung conditions through research in several complementary areas including i) Regenerative Medicine, led by Prof Ludovic Vallier (Cambridge Stem Cell Institute; WT Sanger Institute) and Dr Emma Rawlins (WT Gurdon Institute); ii) Novel anti-inflammatory therapies (at preclinical and clinical stages of evaluation); iii) Remote monitoring, as lead site for the CF Trust-funded National SmartCare Study; iv) our bacterial research on Pseudomonas (c/w Dr Martin Welch, Biochemistry Cambridge), S. aureus, M. abscessus; v) Whole exome sequencing study of non-CF bronchiectasis; and vi) our Clinical trials team at Papworth Hospital.
Development of novel therapeutics
We are engaged in developing novel therapeutic compounds to treat drug resistant bacterial infections using a number of parallel approaches:
i) Together with Sir Mark Welland’s team at the Nanoscience Centre (University of Cambridge), we are exploring how to create nanoparticles containing antibiotics to combat tuberculosis and nontuberculous mycobacteria.
ii) In collaboration with Professor Sir Tom Blundell (Biochemistry; Cambridge) and Professor Chris Abell (Chemistry; Cambridge) we are using Fragment-based drug discovery approaches and developing novel structure- directed applications to develop novel antibiotics for abscessus.
iii) We are exploring a variety of approaches to enhanced innate immunity through stimulating autophagy, increasing lysosomal function, and regulating Pattern recognition receptor signaling.
Related publications:
Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. Schiebler M, […], Floto RA. EMBO Mol Med. 2014 Dec 22;7(2):127-39. PMID: 25535254