ML
Research Interests
Staphylococcus aureus innate immune evasion
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A primary host response to S. aureus infection occurs via complement. Complement is an elegant, evolutionarily conserved system, playing essential roles in early defences by working in concert with immune cells to survey, label and destroy microbial intruders and coordinate inflammation. S. aureus is known to possess a sophisticated anti-complement virulence arsenal expressing both secreted and cell- wall anchored complement evasins. Our research focuses on several different aspects aimed at unravelling the virulence network behind complement resistance in S. aureus.
We employ novel in vitro complement activation/deposition and serum survival assays as well as mutagenesis and flow cytometry to unravel the contribution of specific virulence factors to complement evasion. Secondly, we have developed a functional genomics approach, combining novel complement evasion phenotype testing and genome-wide association studies (GWAS) to identify genes and regulatory networks associated with complement evasion.
Working with our colleagues we are developing cutting edge therapeutics to interrupt bacterial immune evasion mechanisms, designed to re-sensitise pathogens to innate immunity and thus enhancing bacterial elimination. With respect to S. aureus, there are numerous unanswered questions surrounding how this major human pathogen interacts and evades complement. Elucidation of such molecular mechanisms will deepen our understanding of the pathogenic capacity of S. aureus, illuminating key features to target for therapeutic intervention.
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S. aureus antimicrobial resistance and drug discovery
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In collaboration with Dr Michaela Serpi (Cardiff University) we are developing novel 1,3,4-oxadiazoyl based lipoteichoic acid (LTA) inhibitors. LTA are glycopolymeric structures that form an integral part of the Gram-positive cell envelope and are central for bacterial viability and virulence. Therefore, the LTA biosynthetic pathway represents promising drug targets. We have developed novel analogues of the small molecule LTA inhibitor, compound 1771 which display significantly improved activity. Current focus is on developing new and more stable compounds and to determine the precise mechanism of action of these molecules.
Secondly, we are developing novel linear polyamine molecules which show potent ant-staphylococcal activity. S. aureus is unique in that it displays hypersensitivity to naturally occurring polyamines at high concentrations. Our synthetic polyamine (AHA-1394) exhibits a greater than 128-fold increase in activity compared to natural polyamines while maintaining limited toxicity. We are interested in understanding the molecular action of these compounds alone and in conjunction with clinically used antibiotic where they show exceptionally synergy.
Lasty, we are interested in exploring daptomycin resistance in S. aureus. Specifically, we aim to characterise the specific contribution of common mprF and non-mprF polymorphisms that result in daptomycin non-susceptibility by employing gold standard molecular biology and biophysical techniques.
Unravelling virulence mechanisms in S. aureus and Staphylococcus epidermidis
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S. aureus encodes a multitude of virulence determinants, however the secretion of cytolytic toxins and proteases are central components of this arsenal. We are interested in examining the regulatory virulence networks that control toxin and protease expression in S. aureus. Here we employ virulence phenotype assays, mutagenesis, promoter fusion technology and flow cytometry to deepen our molecular understanding behind virulence. We are interested in exploring the relationship between nutrient limitation and toxin/protease expression, identifying key metabolites and environmental signals that alter global virulence regulatory networks enhancing virulence.
Staphylococcus epidermidis is a common commensal bacterium of the human skin and mucosa however in recent years it has become recognized as a major nosocomial pathogen linked with several healthcare associated infections. Despite the importance of this pathogen, we know very little about the molecular details underlying infection biology and resistance to host immune responses and antibiotics. In response we are examining the molecular features required for S. epidermidis resistance to innate immune molecules such as antimicrobial peptides and fatty acids.
Phospholipid nanocapsules for bacterial detection
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Rapid and accurate identification of pathogenic bacteria is the holy grail of diagnostic microbiology. In collaboration with Prof Toby Jenkins (Bath) we are exploring novel methods of detecting bacteria pathogens. Jenkins Group employ hydrogel wound dressings which respond to cytolytic toxins expressed by bacteria in the wound/infection environment. This collaboration aims to extend the utility of these hydrogel system for pre-natal infection detection of the major neonatal pathogen Group B Streptococcus (GBS).
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