Molecular probes for the study of PIMs biosynthesis – MolProPIMS

Phosphatidyl-myo-inositol mannosides (PIMs) are essential components of the cell wall of mycobacteria. Their biosynthesis starts with the transfer of a mannopyranosyl residue from GDP-Man to the inositol ring of phosphatidylinositol catalyzed by the mannosyltransferase PimA. Then a second mannopyranosyl residue is transferred by another mannosyltransferase PimB, followed by an acylation step catalyzed by the acyltransferase PatA. The objective of this proposal is the study of PIMs biosynthesis using novel molecular probes as analogs of acceptor and donor substrates or inhibitors of PimA and PatA. Our long-term goal is the discovery of novel anti-TB drugs targeting PimA and/or PatA in the context of resistance to antibiotics. To this end, we will use an integrated approach in the form of chemistry, protein biochemistry, X-ray crystallography and medicinal chemistry to achieve this goal. Thus, our specific objectives are (i) to identify potent inhibitors of PimA and PatA and (ii) to complete our understanding of the molecular mechanism of substrate/membrane recognition of PimA/PatA, to facilitate the rational design of inhibitors.