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.
We are unravelling the genetic regulatory mechanisms that govern complement evasion and determining what environmental factors trigger the anti-complement response employed by S. aureus.
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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Developing novel antimicrobial compounds​
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Project 1: Oxadiazole-based small molecule inhibition of lipoteichoic acids (LTAs). LTAs are core glycopolymeric structures that form an integral part of the Gram-positive cell envelope and are central for bacterial viability and virulence. Our current focus is on developing new and more stable small molecules and to determine the precise mechanism of action of this novel class of antibiotic.
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Project 2: Synthetic linear polyamines as novel anti-staphylococcal antimicrobials.
S. aureus is unusually sensitive to natural polyamines, and our synthetic analogue AHA-1394 shows over 128-fold greater activity with low toxicity to human cells. Our current focus is fully characterising the molecular mechanism of action, PK/PD parameters and in vivo activity.
Unravelling virulence mechanisms in S. aureus
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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 virulence factor expression, identifying key metabolites and environmental signals that alter global virulence regulatory networks enhancing virulence.
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