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Protein-protein interactions within the Fatty Acid Synthase-II system of Mycobacterium tuberculosis are essential for mycobacterial viability

Abstract : Despite the existence of efficient chemotherapy, tuberculosis remains a leading cause of mortality worldwide. New drugs are urgently needed to reduce the potential impact of the emergence of multidrug‐resistant strains of the causative agent Mycobacterium tuberculosis (Mtb). The front‐line antibiotic isoniazid (INH), and several other drugs, target the biosynthesis of mycolic acids and especially the Fatty Acid Synthase‐II (FAS‐II) elongation system. This biosynthetic pathway is essential and specific for mycobacteria and still represents a valuable system for the search of new anti‐tuberculous agents. Several data, in the literature, suggest the existence of protein–protein interactions within the FAS‐II system. These interactions themselves might serve as targets for a new generation of drugs directed against Mtb. By using an extensive in vivo yeast two‐hybrid approach and in vitro co‐immunoprecipitation, we have demonstrated the existence of both homotypic and heterotypic interactions between the known components of FAS‐II. The condensing enzymes KasA, KasB and mtFabH interact with each other and with the reductases MabA and InhA. Furthermore, we have designed and constructed point mutations of the FAS‐II reductase MabA, able to disrupt its homotypic interactions and perturb the interaction pattern of this protein within FAS‐II. Finally, we showed by a transdominant genetic approach that these mutants are dominant negative in both non‐pathogenic and pathogenic mycobacteria. These data allowed us to draw a dynamic model of the organization of FAS‐II. They also represent an important step towards the design of a new generation of anti‐tuberculous agents, as being inhibitors of essential protein–protein interactions.
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Romain Veyron-Churlet, Olivier Guerrini, Lionel Mourey, Mamadou Daffé, Didier Zerbib. Protein-protein interactions within the Fatty Acid Synthase-II system of Mycobacterium tuberculosis are essential for mycobacterial viability. Molecular Microbiology, Wiley, 2004, 54 (5), pp.1161-1172. ⟨10.1111/j.1365-2958.2004.04334.x⟩. ⟨hal-03004144⟩

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