Download Inhibitors of a microbial metabolic pathway as potential antibiotics

STudent REseArch Mobility Programme(STREAM)
Project proposal
Host University:
Université Paris-Sud
Field (drop-down list):
Natural sciences, mathematics and statistics
Specified field, subject:
Enzymes and Inhibitors
Research project title:
Inhibitors of a microbial metabolic pathway as potential antibiotics
Possible starting month(s):
Sep Oct Nov Dec Jan
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Alternatively, exact starting and end date: from
Suitable for students in:
☐ Bachelor level
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X Master level
Prerequisites:
Training in biochemistry, possibly interesting for chemists interested in biology
Restrictions:
None
Description (maximum 2,000 characters):
Resistance of microbial pathogens to antibiotics represents a global
threat for public health. Antibiotics and antifungal agents usually target either
cell wall formation, general protein synthesis or DNA replication. Innovative
molecules against new targets are urgently needed.
We propose to find inhibitors of a microbial metabolic pathway that
has not been explored for this purpose thus far. The lactate metabolic
pathway is present in many microorganisms. The literature shows an
important role, in the growth and pathogenicity of several bacteria, of the Llactate present in the host fluids and in phagocytic cells. The pathway, well
described in E. coli, includes four proteins, two of which are easily
amenable to a search for inhibitors. These flavin-dependent enzymes are
an L-lactate dehydrogenase (fLLDH) and a D-lactate dehydrogenase
(fDLDH), that are membrane bound, both linked to the respiratory chain;
the latter is necessary for the active transport of many metabolites. The
genes of these enzymes have a high sequence identity in many bacteria, in
particular enterobacteria.
The proposed work includes cloning the gene of the E. coli fLLDH,
expressing the protein, identifying inhibitors by screening the chemical
libraries available at the national level. and analysing the effect of the
selected hits on the growth of relevant bacteria. The human genome has two
genes for soluble peroxisomal proteins with some similarity to the fLLDH;
their physiological substrate is not lactate. Tests on these enzymes with the
interesting hits will eliminate the unspecific molecules. Previous work
(published in part) has shown that one can find specific and unspecific
inhibitors. This proposal is part of a larger project; it includes similar work
with the fDLDH, chemical synthesis for improving the affinities and testing
the effect of the hits on microbial resistance to ingestion and killing by
phagocytic cells. Competence for all these tasks is present in the Biophysics
group.
Faculty and/or Department:
Laboratoire de Chimie Physique, CNRS UMR 8000, Biophysics group.
Contact person, including position:
Séverine Fogel, Head of International Relations
Contact email:
[email protected]
Deadline for nomination to reach host university:
2 months before the starting date
Notification of admission given by the end of:
Within 3 weeks
Additional information: