This Week in TB R&D – 5 April 2010

5 Apr 2010
by Working Group

Many antibiotics used today to fight and control M. tb infection target cell wall synthesis or DNA replication, and related pathogen growth mechanisms. A recent report by Zhou et al. in PNAS at the beginning of year, suggested an alternate mechanism for M. tb elimination; targeting MptpB, a mycobacterium specific protein tyrosine phosphatase.

Tuberculosis drugs and actions

Brief MptpB background

Crystal Structure Of Mycobacterium Tuberculosis Protein Tyrosine Phosphatase Ptpb In Complex With The Specific Inhibitor Omts.

M.tb encodes two protein tyrosine phosphatases, MptpA and MptpB, in its genome. Characterization of MptpB by Koul et al. suggested that MptpB was secreted by M. tb laboratory strains H37Rv and H37Ra, and solely expressed in M. tb complex stains but not M. smegmatis, a mycobacterium that does not cause tuberculosis. In 2003, Singh et al. demonstrated that an M. tb stain carrying a mutated MptpB gene was less virulent than the wild-type strain in infected macrophages and guinea pigs. Interestingly, the decrease in virulence of the MptpB mutant strain was only observed in ‘activated’ macrophages, macrophages stimulated by interferon-gamma (a cytokine).

Grundner et al. in 2007 published the crystal structure of MptpB complexed with a selective competitive inhibitor, (oxalylamino-methylene)-thiophene sulfonamide (OMTS). The structure provided insight into rational drug design for this protein tyrosine phosphatase. In 2009, Beresford et al. utilized a salicylate library in an attempt to identify specific inhibitors for MptpB. The authors identified two competitive MptpB inhibitors that displayed effects on M. tb infected macrophages.

PNAS paper

In the paper by Zhou et al., the authors overexpressed MptpB in macrophages in an attempt to find out which signaling pathways may be affected by MptpB presence to account for bacterial survival. Overexpression of MptpB appears to result in the dephosphorylation of ERK1/2 and p38, an increase in phosphorylation of Akt, and reduction of IL-6 production in interferon-gamma stimulated cells. Furthermore, increased in cell numbers were observed in an assay to evaluate apoptosis, the mechanism of which was not clear. Using click-chemisty, the authors describe the identification of an MptpB specific non-competitive inhibitor, I-A09. In macrophages overexpressing MptpB, I-A09 was able to antagonize the previously observed changes in ERK1/2 and Akt phosphorylation, as well as IL-6 production.

The key figure of the paper however was Figure 7, which showed that I-A09 treatment was able to reduce bacterial load in macrophages infected with M. tb. This figure also presented data which may suggest the drug is able to reduce bacterial load in non-activated or interferon-gamma stimulated macrophages. This result is different from previously published data noted above which suggested that the loss of MptpB only affected virulence in ‘activated’ macrophages. Future work needs to evaluate the effects of this drug in vivo.

Is MptpB a major virulence factor? Why does overexpression of MptpB result in an increase in cell number? If I-A09 displays effects in non-activated macrophages, is it possibly affecting other host:pathogen survival mechanisms? Please add your comments.

More News
19 Mar 2024
For World TB Day 2024, the WGND is spotlighting a monumental achievement in TB drug research and development: the Global TB Drug Pipeline has never been bigger than it is today. The number of drug candidates being clinically evaluated for use in the treatment of adult pulmonary TB has surpassed...
3 Aug 2023
The Working Group on New TB Drugs, in collaboration with the New Diagnostics Working Group, Working Group on New Vaccines, FIND, IAVI, and TB Alliance, is co-hosting a New Tools Summit at the Marriot Champs Elysée Hotel in Paris, France on Tuesday, 14 November 2023. The WGND Annual Meeting will be...
23 Aug 2022
The PAN-TB collaboration announced initial plans for a Phase 2 clinical trial evaluating two novel drug regimens to treat Tuberculosis. Sponsored by the Bill and Melinda Gates Foundation, the PAN-TB, or “Project to Accelerate New Treatments for Tuberculosis”, collaboration brings together non-...