# MmpL3 as a target for novel anti-TB agents

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2021 · $630,615

## Abstract

Summary
Mycolic acids are essential building blocks of the outer membrane of all mycobacteria and the interest in drugs
targeting their biosynthesis and export is clearly illustrated by the therapeutic efficacy of several past and
present anti-mycobacterial agents including isoniazid, ethionamide, thiacetazone and isoxyl, and a number of
recently discovered small molecule inhibitors reported to inhibit the integral membrane mycolic acid
transporter, MmpL3. Joint efforts by our Consortium prior to and during the previous funding period have led to
the discovery of MmpL3 and to the validation of this transporter as a target of therapeutic interest. These
studies further allowed us to gain the first insights into its structure, energetics and mechanisms of
susceptibility and resistance to inhibitors.
Despite these advances, important gaps still remain in our understanding of the translocation of mycolic acids
from the cytoplasm to the periplasm and outer membrane, the precise role played by MmpL3 in this process,
and the molecular mechanisms involved. Several lines of evidence indicate that the export of mycolic acids to
the cell surface involves more components than the only MmpL3 protein, and that MmpL3 may act as a
scaffold for a multiprotein complex coupling synthesis and export. Our preliminary evidence further indicates
that MmpL3 may play a role in coordinating, at the level of the plasma membrane, the focal deposition of cell
wall core constituents during cell elongation and cell division.
Aim 1 of this basic research proposal is to define the nature of the MmpL3-associated machinery responsible
for the efficient synthesis and export of mycolic acids in Mycobacterium tuberculosis, and to probe the
involvement of MmpL3 in the spatiotemporal coordination of new cell wall deposition during cell elongation and
division. Under Aim 2, a detailed biochemical examination of MmpL3 will be conducted to delineate the precise
extent of mycolic acid transport mediated by MmpL3 in mycobacterial cells and to gain insight in the molecular
mechanisms involved. The assays developed under this aim will further be used to probe the precise
mechanism of action of MmpL3 inhibitors and associated mechanisms of resistance.
In addition to providing fundamental knowledge about essential physiological processes of all mycobacteria,
the results from these studies will facilitate current drug development efforts targeted to MmpL3 and could
further lead to innovative therapeutic strategies targeting key metabolic processes at the intersection of cell
envelope biosynthesis and cell elongation and division.

## Key facts

- **NIH application ID:** 10144927
- **Project number:** 5R01AI116525-06
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Mary Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $630,615
- **Award type:** 5
- **Project period:** 2015-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144927

## Citation

> US National Institutes of Health, RePORTER application 10144927, MmpL3 as a target for novel anti-TB agents (5R01AI116525-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144927. Licensed CC0.

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