MmpL3, the exporter of trehalose monomycolate, a key cell-wall component. We determined the kill kinetics of the lead indolcarboxamide NITD-349 and determined that while kill was rapid against low-density cultures, bactericidal activity was inoculum-dependent. A combination of NITD-349 with isoniazid (which inhibits mycolate synthesis) had an increased kill rate; this combination prevented the appearance of resistant mutants, even at higher inocula.

01 Sep 2022·Chemistry & Biodiversity

Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb

Article

Author: Kwofie, Samuel K. ; Yeboah, Omane P. ; Wilson, Michael D. ; Mensah, Francis A. ; Hanson, George ; Nortey, Richmond T. ; Sasu, Henrietta ; Enninful, Kweku S. ; Agoni, Clement

AbstractMycobacterial membrane proteins Large (MmpLs), which belong to the resistance, nodulation, and division (RND) protein superfamily, play critical roles in transporting polymers, lipids, and immunomodulators. MmpLs have become one of the important therapeutic drug targets to emerge in recent times. In this study, two homology modelling techniques, Modeller and SWISS‐MODEL, were used in modelling the three‐dimensional protein structure of the MmpL3 of Mycobacterium tuberculosis using that of M. smegmatis as template. MmpL3 inhibitors, namely BM212, NITD304, SPIRO, and NITD349, in addition to the co‐crystalized ligands AU1235, ICA38, SQ109 and rimonabant, were screened against the modelled structure and the Mmpl3 of M. smegmatis using molecular docking techniques. Protein‐ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson‐Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.

01 Jul 2020·Journal of Molecular BiologyQ2 · BIOLOGY

Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and SPIRO

Q2 · BIOLOGY

Article

Author: Yang, Xiaolin ; Zhang, Bing ; Hu, Tianyu ; Rao, Zihe ; Yang, Haitao ; Guddat, Luke W ; Xu, Wenqing ; Yang, Xiuna

Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3.

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Indication	Highest Phase	Country/Location	Organization	Date
Mycobacterium Tuberculosis, Susceptibility to Infection By	Discovery	SG	Novartis Institute for Tropical Diseases Pte Ltd.	04 Dec 2013

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