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Micrococcin P1-A bactericidal thiopeptide active against Mycobacterium tuberculosis
Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
Queen Mary Univ London, London E1 2AD, England.;UCL, Div Infect & Immun, Ctr Clin Microbiol, London, England..
Sanofi Aventis R&D, Drug Disposit, F-69367 Lyon, France..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
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2016 (English)In: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 100, 95-101 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 100, 95-101 p.
Keyword [en]
Tuberculosis, Drug development, Translation, Thiopeptides
National Category
Cell and Molecular Biology Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:uu:diva-307870DOI: 10.1016/j.tube.2016.07.011ISI: 000382201400013PubMedID: 27553416OAI: oai:DiVA.org:uu-307870DiVA: diva2:1048887
Funder
EU, FP7, Seventh Framework Programme, 260872Swedish Research Council, 2014-4423
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2016-11-22Bibliographically approved

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