Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/116940
Title: Micrococcin P1 - A bactericidal thiopeptide active against Mycobacterium tuberculosis
Authors: Degiacomi, Giulia 
Personne, Yoann
Mondésert, Guillaume
Ge, Xueliang
Mandava, Chandra Sekhar
Hartkoorn, Ruben C
Boldrin, Francesca 
Goel, Pavitra
Peisker, Kristin
Benjak, Andrej
Barrio, Maria Belén
Ventura, Marcello 
Brown, Amanda C
Leblanc, Véronique
Bauer, Armin
Sanyal, Suparna
Cole, Stewart T
Lagrange, Sophie
Parish, Tanya
Manganelli, Riccardo 
Keywords: Drug development;Thiopeptides;Translation;Tuberculosis
Keywords Plus: DRUG-RESISTANT TUBERCULOSIS;ANTIBIOTICS;THIOSTREPTON;RIBOSOME;SITE;L11
Mesh headings: Antibiotics, Antitubercular;Bacteriocins;Mycobacterium tuberculosis;Peptides
Secondary Mesh headings: Animals;Bacterial Proteins;Cells, Cultured;Colony Count, Microbial;Dose-Response Relationship, Drug;Drug Discovery;Drug Evaluation, Preclinical;Drug Resistance, Bacterial;Humans;Macrophages;Microbial Sensitivity Tests;Mutation;Peptide Chain Elongation, Translational;Ribosomal Proteins
Issue Date: 2016
Publisher: CHURCHILL LIVINGSTONE
Journal: Tuberculosis (Edinburgh, Scotland) 
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.
URI: http://hdl.handle.net/20.500.12857/116940
ISSN: 14729792
DOI: 10.1016/j.tube.2016.07.011
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