Professor Sarah Coulthurst
Research
Overall our research aims to elucidate how Gram-negative bacterial pathogens are able to successfully cause disease. This should provide both an improved understanding of basic biological processes and, ultimately, contribute to novel therapeutic antimicrobial strategies. We would like to understand how bacteria interact with different types of organisms, including themselves and their direct competitors, and how such interactions provide fitness advantages.
We are interested in several inter-linked research areas:
1. Protein secretion systems
Protein secretion systems are molecular machines used by bacterial cells to translocate specific sets of proteins out of the bacterial cell, either to the extracellular milieu or directly into target cells (eukaryotic or prokaryotic). Secretion systems, and the diverse proteins that they secrete, have long been known as key virulence factors against eukaryotic host organisms. However is becoming increasingly recognised that protein secretion systems can also be important mediators of competition between bacterial cells, by delivering diverse and effective anti-bacterial toxins.
Our largest research area is the Type VI secretion system (T6SS), which is widespread in Gram-negative bacteria and is a complex, dynamic nanomachine which ‘fires’ toxic effector proteins into target cells. Most commonly, the target is rival bacterial cells, making the T6SS a key player in inter-bacterial competition and competitive fitness, and therefore an indirect virulence factor. Additionally, we have recently shown that the T6SS can also be used to deliver specific anti-fungal affectors against microbial fungal competitors, implying a broad role for this system in shaping polymicrobial communities. In some cases, the T6SS can also act as a classical virulence factor, delivering effectors into eukaryotic host cells, and in others, effectors can act extracellularly to scavenge scarce metal ions. Thus this is a highly versatile machinery to mediate bacterial interactions with other cells and the environment.
We are interested in the molecular mechanisms, role and regulation of the T6SS machinery, but also in the identification and characterisation of new anti-microbial toxins secreted by the system. For many of our studies we use the anti-bacterial and anti-fungal T6SS of the opportunistic pathogen Serratia marcescens as a model system.
2. Mechanisms of inter-bacterial competition
Competitive interactions between different strains and species of bacteria, and between bacteria and microbial fungi, are widespread and key to defining the polymicrobial communities in which most bacteria exist. A potential pathogen must be able to compete against host microflora, other pathogens and other residents of environmental reservoirs in order to mount a successful infection. Multiple mechanisms of competition exist, both contact-dependent, such as the Type VI secretion system, and contact-independent, such as the production of diffusible secondary metabolites, including classical antibiotics. In addition to our work on the T6SS we are also interested in the production of antimicrobial secondary metabolites and other inhibitory systems in strains of Serratia marcescens and related organisms. More broadly, I have had a long-standing interest in inter-bacterial interactions, including past work on quorum sensing in pathogenic Enterobacteriaceae.
3. Integration of molecular, cellular and ‘omics approaches to study bacterial interactions
We study a number of Gram-negative bacterial pathogens, mostly members of the Enterobacteriaceae which represent opportunistic human pathogens, for example Serratia marcescens, E. coli and Enterobacter. We are a molecular microbiology group, utilising a variety of approaches, including genetics, molecular biology, classical microbiology, biochemistry, structural biology, cell biology, genomics and proteomics.
Teaching
BS42009, Advanced Molecular Microbiology – Module Manager and contributor
BS32004, Molecular Microbiology - contributor
Honours Year – annual research project supervisor
Integrated MSci – project supervisor
Publications
Selected publications:
Hernandez, R.E., Gallegos Monterrosa, R., Coulthurst, S.J. (2020). Type VI secretion system effector proteins: effective weapons for bacterial competitiveness. Cell Microbiol, 22, e13241
Interview with Dr Sarah Coulthurst. Cell Microbiol, 22, e13233.
Mariano, G., Trunk, K., Williams, D.J., Monlezun, L., Strahl, H., Pitt, S.J. & Coulthurst, S.J. (2019). A family of Type VI secretion system effector proteins that form ion-selective pores. Nature Communications, 10, 5484. (Research Highlights article: Nature Reviews Microbiology 18, 62–63).
Coulthurst, S.J. (2019) The Type VI secretion system: a versatile bacterial weapon. Microbiology, 165, 503–515.
Trunk, K., Peltier, J., Liu, Y., Dill, B.D., Walker, L., Gow, N.A.R., Stark, M.J.R., Quinn, J., Strahl, H., Trost, M. & Coulthurst, S.J. (2018) The Type VI secretion system deploys anti-fungal effectors against microbial competitors. Nature Microbiology, 3, 920–931. (News and Views article: Nature Microbiology 3, 860–861)
Ostrowski, A., Cianfanelli, F.R., Porter, M., Mariano, G., Peltier, J., Wong, J., Swedlow, J.R., Trost, M. and Coulthurst, S.J. (2018) Killing with proficiency: integrated post-translational regulation of an offensive Type VI secretion system. PLoS Pathogens, 14, e1007230.
Mariano, M., Monlezun, L. & Coulthurst, S.J. (2018) Dual role for DsbA in attacking and targeted bacterial cells during Type VI secretion system-mediated competition. Cell Reports, 22, 774–785.
Cianfanelli, F.R., Alcoforado Diniz, J., Guo, M., De Cesare, V., Trost, M. & Coulthurst, S.J. (2016) VgrG and PAAR proteins define distinct versions of a functional Type VI secretion system. PLoS Pathogens, 12, e1005735.
Cianfanelli, F.R., Monlezun, L. & Coulthurst, S.J. (2016) Aim, Load, Fire: The Type VI Secretion System, a Bacterial Nanoweapon. Trends Microbiol, 24, 51-62.
Gerc, A.J., Diepold, A., Trunk, K., Porter, M., Rickman, C., Armitage, J.P., Stanley-Wall, N.R. & Coulthurst, S.J. (2015) Visualization of the Serratia Type VI Secretion System Reveals Unprovoked Attacks and Dynamic Assembly. Cell Reports, 12, 2131-42.
Alcoforado Diniz, J. & Coulthurst, S.J. (2015) Intra-species Competition in Serratia marcescens is Mediated by Type VI-Secreted Rhs Effectors and a Conserved Effector-Associated Accessory Protein. J Bacteriol, 197, 2350-60.
Hamilton, J.J., Marlow, V.L., Owen, R.A., Costa, M.de A., Guo, M., Buchanan, G., Chandra, G., Trost, M., Coulthurst, S.J., Palmer, T., Stanley-Wall, N.R., & Sargent, F. (2014) A holin and an endopeptidase are essential for chitinolytic protein secretion in Serratia marcescens. J Cell Biol, 207, 615-26.
Iguchi, A., Komatsu, H., Nagaya, Y., Pradel, E., Ooka, T., Ogura, Y., Katsura, K., Kurokawa, K., Oshima, K., Hattori, M., Parkhill, J., Sebaihia, M., Coulthurst, S.J., Gotoh, N., Ewbank, J.E., Thomson, N.R. & Hayashi, T. (2014) Genome evolution and plasticity of Serratia marcescens, an important multidrug resistant nosocomial pathogen. Genome Biol Evol, 6, 2096-110.
Gerc A.J., Stanley-Wall N.R. & Coulthurst S.J. (2014) The role of the phosphopantetheinyl transferase enzyme, PswP, in the biosynthesis of antimicrobial secondary metabolites by Serratia marcescens Db10. Microbiology 160, 1609-17.
English G., Byron O., Cianfanelli F.R., Prescott A.R., & Coulthurst S.J. (2014) Biochemical analysis of TssK, a core component of the bacterial Type VI secretion system, reveals distinct oligomeric states of TssK and identifies a TssK-TssFG subcomplex. Biochem J, 461, 291-304.
Fritsch M.J., Trunk K., Alcoforado Diniz J., Guo M., Trost M. & Coulthurst, S.J. (2013) Proteomic identification of novel secreted anti-bacterial toxins of the Serratia marcescens Type VI secretion system. Mol Cell Proteomics, 12, 2735-49.
Srikannathasan V., English G., Bui, N.K., Trunk K., O’Rourke P.E.F., Rao V.A., Vollmer W., Coulthurst S.J. & Hunter W.N. (2013) Structural basis for Type VI secreted peptidoglycan DL-endopeptidase function, specificity and neutralization in Serratia marcescens. Acta Crystallogr D, 69, 2468-82.
English, G., Trunk, K., Rao, V.A., Srikannathasan, V., Hunter, W.N. & Coulthurst, S.J. (2012) New Secreted Toxins and Immunity Proteins Encoded within the Type VI Secretion System Gene Cluster of Serratia marcescens. Mol Microbiol, 86, 921-936.
Gerc, A.J., Song, L., Challis, G.L., Stanley-Wall, N.R. & Coulthurst, S.J. (2012) The insect pathogen Serratia marcescens Db10 uses a hybrid non-ribosomal peptide synthetase-polyketide synthase to produce the antibiotic althiomycin. PLoS One, 7:e44673.
Murdoch, S.L., Trunk, K., English, G., Fritsch, M.J., Pourkarimi, E. & Coulthurst, S.J. (2011) The opportunistic pathogen Serratia marcescens utilises Type VI Secretion to target bacterial competitors. J Bacteriol, 193, 6057-69.
Rao, V.A., Shepherd, S.M., English, G., Coulthurst, S.J. & Hunter, W.N. (2011) The structure of Serratia marcescens Lip; a membrane bound component of the Type VI secretion system. Acta Crystallogr D Biol Crystallogr, 67, 1065-1072.
Coulthurst, S. J., Lilley, K. S., Hedley, P. E., Lui, H., Toth, I. K., & Salmond G. P. C. (2008) DsbA plays a critical and multifaceted role in the production of secreted virulence factors by the phytopathogen, Erwinia carotovora subsp. atroseptica. J Biol Chem, 283, 23739-23753.
Liu, H., Coulthurst S. J., Pritchard L., Hedley P., Ravensdale M., Humphris S., Burr T., Takle G., Birch P. R. J., Salmond G. P. C. & Toth I. K. (2008) Quorum sensing coordinates brute force and stealth modes of infection in the plant pathogen Pectobacterium atrosepticum. PLoS Pathog. 20, e1000093.
Coulthurst, S. J., Clare, S., Evans, T. J., Foulds, I. J., Roberts, K. J., Dougan, G. & Salmond, G. P. C. (2007) Quorum sensing plays an unexpected role in virulence in the model pathogen, Citrobacter rodentium. EMBO Reports, 8, 698-703.
Coulthurst, S. J., Williamson, N. R., Harris, A. K., Spring, D. R. & Salmond, G. P. C. (2006). Metabolic and regulatory engineering of Serratia marcescens: mimicking phage-mediated horizontal acquisition of antibiotic biosynthesis and quorum sensing capacities. Microbiology, 152, 1899-1911. (Research Highlights article: Nature Reviews Microbiology, 4, 570)