About GUTMICROSUL
GUTMICROSUL involves a detailed study of the membrane complex DsrMKJOP, essential for sulfide production by gut bacteria, a process associated with dysbiosis and disease. DsrMKJOP is common to most groups of sulfidogenic bacteria and is an attractive target for their inhibition, which has not been investigated before. This complex is also central in the metabolism of sulfur-dissimilating environmental bacteria, and unravelling its mechanism will enable the development of inhibitors to prevent build-up of sulfide in the gut and the environment. In addition, it will also be a scientific landmark in microbial physiology of anaerobes.
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GUTMICROSUL proposes a multidisciplinary and comprehensive work plan involving a range of in vivo and in vitro methodologies, including genetic, microbiologic, biochemical, structural and biophysical techniques, to understand the functional mechanism of DsrMKJOP and discover efficient inhibitors. This work plan is very feasible and will lead us to the desired results, paving the way for a successful drug-development pipeline targeting the overgrowth of sulfidogenic bacteria in the gut.
The work plan involves producing recombinant DsrMKJOP for biochemical, functional, structural and biophysical studies, and also variants with key mutations for mechanistic studies. The effect of these mutations on growth will also be assessed by in vivo studies. We will investigate how the complex interacts with and reduces the substrate DsrC-T, if it is electrogenic and capable proton pumping, and what is the mechanism of energy conservation involving the two quinone binding sites. Finally, we will study inhibition of the complex, based on inhibitors of quinone binding, by catalytic assays, in silico modelling and in vivo assays with two gut bacteria.