Secreted virulence factors: evolution, ecology and therapeutic manipulation
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Date
28/06/2016Item status
Restricted AccessEmbargo end date
31/12/2100Author
Allen, Richard Charles
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Abstract
Bacterial infections are an increasing cause for concern as resistance spreads
to the majority of our front line antibiotics. To counter antibiotic resistance,
new treatment regimens and drug targets are being investigated, including
directly targeting bacterial virulence (pathogen-induced harm to the host),
and therapies which target resistance mechanisms. The outcome of
successful treatment with these compounds is not always killing or halting
growth of bacteria, therefore selection for resistance to these types of
therapeutics is complex. This complexity is increased by the secretion of
many virulence factors, meaning their effects are shared with neighbouring
individuals. In addition virulence factors show high phenotypic plasticity
due to regulation by processes like quorum sensing (QS), which further
complicates treatments targeting virulence, or the regulatory processes
themselves.
Using the example of quorum sensing inhibitors this study shows the
importance of understanding the function and ecology of targeted virulence
factors, to predict the selection for resistance to anti-virulence drugs. Later
chapters elaborate on this to show how quorum sensing control affects
selection on secreted virulence factors. The use of anti-virulence drugs as
adjuvants is discussed, with a study showing that the interaction between QS
inhibition and translation inhibitors is dependent on the environment. The
selection for resistance to combinations of antibiotics and adjuvants is
investigated using co-amoxiclav as an example, showing that treatment with
high doses of adjuvant are robust to the evolution of resistance.