Micrococcin P1 - A bactericidal thiopeptide active against Mycobacterium tuberculosis.

Abstract

The lack of proper treatment for serious infectious diseases due to the emergence of multidrug resistance reinforces the need for the discovery of novel antibiotics. This is particularly true for tuberculosis (TB) for which 3.7% of new cases and 20% of previously treated cases are estimated to be caused by multi-drug resistant strains. In addition, in the case of TB, which claimed 1.5 million lives in 2014, the treatment of the least complicated, drug sensitive cases is lengthy and disagreeable. Therefore, new drugs with novel targets are urgently needed to control resistant Mycobacterium tuberculosis strains. In this manuscript we report the characterization of the thiopeptide micrococcin P1 as an anti-tubercular agent. Our biochemical experiments show that this antibiotic inhibits the elongation step of protein synthesis in mycobacteria. We have further identified micrococcin resistant mutations in the ribosomal protein L11 (RplK); the mutations were located in the proline loop at the N-terminus. Reintroduction of the mutations into a clean genetic background, confirmed that they conferred resistance, while introduction of the wild type RplK allele into resistant strains re-established sensitivity. We also identified a mutation in the 23S rRNA gene. These data, in good agreement with previous structural studies suggest that also in M. tuberculosis micrococcin P1 functions by binding to the cleft between the 23S rRNA and the L11 protein loop, thus interfering with the binding of elongation factors Tu and G (EF-Tu and EF-G) and inhibiting protein translocation.

DOI: 10.1016/j.tube.2016.07.011

Cite this paper

@article{Degiacomi2016MicrococcinP, title={Micrococcin P1 - A bactericidal thiopeptide active against Mycobacterium tuberculosis.}, author={Giulia Degiacomi and Yoann Personne and Guillaume Mond{\'e}sert and Xueliang Ge and Chandra Sekhar Mandava and Ruben C. Hartkoorn and Francesca Boldrin and Pavitra Goel and Kristin Peisker and Andrej Benjak and Mar{\'i}a Bel{\'e}n Barrio and Marcello Ventura and Amanda Claire Brown and V{\'e}ronique Leblanc and Armin Bauer and Suparna Sanyal and Stewart T Cole and Sophie Lagrange and Tanya Parish and Riccardo Manganelli}, journal={Tuberculosis}, year={2016}, volume={100}, pages={95-101} }