3 research outputs found
Biological and structural characterization of theMycobacterium smegmatis nitroreductase NfnB, and its rolein benzothiazinone resistance
Tuberculosis is still a leading cause of death in developing
countries, for which there is an urgent need
for new pharmacological agents. The synthesis of
the novel antimycobacterial drug class of benzothiazinones
(BTZs) and the identification of their
cellular target as DprE1 (Rv3790), a component of
the decaprenylphosphoryl-b-D-ribose 2'-epimerase
complex, have been reported recently. Here, we
describe the identification and characterization of a
novel resistance mechanism to BTZ in Mycobacterium
smegmatis. The overexpression of the nitroreductase
NfnB leads to the inactivation of the drug by
reduction of a critical nitro-group to an amino-group.
The direct involvement of NfnB in the inactivation of
the lead compound BTZ043 was demonstrated by
enzymology, microbiological assays and gene knockout
experiments. We also report the crystal structure
of NfnB in complex with the essential cofactor flavin
mononucleotide, and show that a common amino
acid stretch between NfnB and DprE1 is likely to be
essential for the interaction with BTZ. We performed
docking analysis of NfnB-BTZ in order to understand
their interaction and the mechanism of
nitroreduction. Although Mycobacterium tuberculosis
seems to lack nitroreductases able to inactivate
these drugs, our findings are valuable for the design
of new BTZ molecules, which may be more effective
in vivo
An ethA-ethR-deficient Mycobacterium bovis BCG mutant displays increased adherence to mammalian cells and greater persistence in vivo, which correlate with altered mycolic acid composition
10.1128/IAI.01332-13Infection and Immunity8251850-1859INFI