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E u r o S c i C o n C o n f e r e n c e o n
Chemistry
2018
Chemistry 2018
Journal of Organic & Inorganic Chemistry
ISSN 2472-1123
F e b r u a r y 1 9 - 2 0 , 2 0 1 8
P a r i s , F r a n c e
Page 72
A
ntimicrobial resistance (AMR) is a growing public health
problem worldwide and tuberculosis is the bacterial
infection most affected by AMR. The estimated global
burden of multi-drug resistant tuberculosis is 450,000 each
year. The most alarming figure is that extensively drug
resistant
Mycobacterium tuberculosis
(
M. tuberculosis
) (XDR-
Mtb) has already been reported in more than 92 countries,
which forces us to develop innovative approaches to revert
resistance. The originality of our approach arises from the
peculiar observation that a significant number of anti-TB
antibiotics are prodrugs, meaning that they become active
inside of the mycobacteria thanks to specific mycobacterial
enzymatic bioactivations, tightly controlled by transcriptional
regulators. Ethionamide (
ETH
), for instance, requires
Teaching old
drugs new tricks:
reprogramming
thioamide’s
bioactivation to fight
multidrug resistant
Mycobacterium
tuberculosis
Nicolas Willand
1
, Marc
Gitzinger
2
, Benoit Deprez
1
and
Alain Baulard
1
1
P Lille University, France
2
BioVersys AG, Switzerland
intracellular activation by a monooxygenase called
EthA
.
EthR
,
a transcriptional repressor (TR), controls the expression of
EthA
and thus limits
ETH
conversion into its active form. Use of
EthR
inhibitors in combination with
ETH
showed a strong effect in
boosting
EthA
production and thus sensitivity to the prodrug.
Using a combination of phenotypic and molecular assays, we
have discovered and optimized a new type of compounds called
SMARt (Small Molecule Aborting Resistance) that are now able
to wake-up cryptic bio-activation pathways of ethionamide,
and consequently revert resistance to the prodrug. Treatment
of a large panel of clinical isolates highly resistant to
ETH
with
the combination of SMARt-420 and
ETH
, allowed inhibiting
growth with MIC below the resistant threshold of 0.5 μg/mL.
In this experiment, SMARt-420 did not only increase the basal
sensitivity of
M. tuberculosis
to ethionamide but also fully
reversed ethionamide acquired resistance. Finally, mice infected
with an ethionamide-resistant mycobacterial strain were also
successfully treated orally with the combination of ETH and
SMARt-420 ( 50 mpk) and a 4.6 log reduction of the bacterial
load in the lun
≈
gs was observed. From our last generation of
SMARt molecules, we have now been able to select a preclinical
candidate.
nicolas.willand@univ-lille2.frJ Org Inorg Chem 2018, Volume: 4
DOI: 10.21767/2472-1123-C1-003