DRUG DISCOVERY AND RESISTANCE
Micrococcin P1 e A bactericidal thiopeptide active against
Mycobacterium tuberculosis
Q7
Q6
Giulia Degiacomi
a, 1
, Yoann Personne
b, 1 , 2
, Guillaume Mond
esert
c
, Xueliang Ge
d
,
Chandra Sekhar Mandava
d
, Ruben C. Hartkoorn
e, 3
, Francesca Boldrin
a
, Pavitra Goel
b
,
Kristin Peisker
d
, Andrej Benjak
e
, Maria Bel
en Barrio
c
, Marcello Ventura
a
,
Amanda C. Brown
b, 4
,V
eronique Leblanc
c
, Armin Bauer
c
, Suparna Sanyal
d
,
Stewart T. Cole
e
, Sophie Lagrange
c
, Tanya Parish
b, 5
, Riccardo Manganelli
a, *
a
Department of Molecular Medicine, University of Padova, Padova, Italy
b
Queen Mary University of London, London E1 2AD, United Kingdom
c
Sanofi-Aventis R&D, Drug Disposition, 69367 Lyon, France
d
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
e
Ecole Polytechnique F ed erale de Lausanne, Global Health Institute, Lausanne, Switzerland
article info
Article history:
Received 21 March 2016
Received in revised form
13 July 2016
Accepted 20 July 2016
Keywords:
Tuberculosis
Drug development
Translation
Thiopeptides
summary
The lack of proper treatment for serious infectious diseases due to the emergence of multidrug resistance
(MDR) 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 MDR-
TB. 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.
© 2016 Elsevier Ltd. All rights reserved.
1. Introduction
Among the infectious diseases affecting mankind, tuberculosis
(TB) still ranks among the deadliest, posing a major threat to the
health of millions of people around the globe [1]. Globalization and
recent trends in migration are changing the epidemiology of TB
worldwide and the emergence of multi-drug resistant (MDR),
extensively Q1 resistant (XDR) [2] and totally resistant (TDR) strains
[3] is raising severe concern among health authorities. The devel-
opment of new drugs, better diagnostics and improved prophy-
lactic measures are urgently needed to control the TB pandemic at a
global level and a better understanding of Mycobacterium
* Corresponding author. Department of Molecular Medicine, University of
Padova, Via Gabelli 63, 35121 Padova, Italy. Fax: þ39 049 8272355.
E-mail address: riccardo.manganelli@unipd.it (R. Manganelli).
1
Contributed equally to the manuscript.
2
Present address: Centre for Clinical Microbiology, Division of Infection and
Immunity, University College London, London, United Kingdom.
3
Present address: Center for Infection & Immunity of Lille, Institut Pasteur de
Lille, INSERM U1019 e CNRS UMR 8204, University of Lille Nord de France, Lille,
France.
4
Present address: Department of Microbiology and Immunology, Cornell Uni-
versity, Ithaca, NY, 14853, United States.
5
Present address: TB Discovery Research, Infectious Disease Research Institute,
Seattle, WA 98102, USA.
Contents lists available at ScienceDirect
Tuberculosis
journal homepage: http://intl.elsevierhealth.com/journals/tube
http://dx.doi.org/10.1016/j.tube.2016.07.011
1472-9792/© 2016 Elsevier Ltd. All rights reserved.
Tuberculosis xxx (2016) 1e7
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Please cite this article in press as: Degiacomi G, et al., Micrococcin P1 e A bactericidal thiopeptide active against Mycobacterium tuberculosis,
Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.07.011