Principal Investigator (PI)
The Foundation is providing £223,178 in support.
Dr. Thomas Wiggins
GSK R&D contributes with the following:
1. A large compound library (75,000+) to screen for activity against MetX
2. The high-throughput screening facility capable of screening a large compound library (75,000+)
3. The technical expertise to perform the high-throughput screening
4. The scientific expertise on how to perform a drug discovery program to identify compounds with improved activity to proceed into a drug development program. For example, the in silico medicinal chemistry team can model hit compounds into our MetX structures to identify more potent analogues.
5. The scientific expertise to assist with compound progression to in vivo studies (e.g. how to perform safety and pharmacokinetic studies).
One of the biggest challenges with Mycobacterium tuberculosis (Mtb) drug discovery is the identification of drugs that sterilize Mtb cultures. We have recently identified the methionine biosynthetic pathway as a promising new target space for the development of new anti-tuberculosis drugs.
A methionine auxotroph was generated through the genetic deletion of the MetX gene (homoserine transacetylase), which is responsible for the first dedicated step of the methionine biosynthetic pathway. We have shown that the ∆metX strain is rapidly sterilized in vitro and is avirulent in both immunocompetent and immunocompromised mice (1).
By using a conditional knockdown system, we show that Mtb is unable to scavenge methionine from the host and chronic infections are rapidly sterilized (2). Together, these results highlight that MetX is a promising new drug target to sterilize all populations of Mtb.
This project aims to identify potent inhibitors of MetX with in vivo efficacy to be further progressed as lead compounds.
Firstly, we will optimize our current MetX activity assay to be compatible with the Tres Cantos high throughput screening facility. Using this assay, the GSK 75,000 chemical diversity compound library will be screened for compounds that inhibit MetX.
Hits will be validated by testing activity in vitro against our MetX conditional knockdowns. Validated compounds will serve as scaffolds for selection of addition compounds to screen for activity. This will be aided by the Tres Cantos computational medicinal chemistry team.
Lead compounds will then be further assessed for cytotoxicity and routine TB profiling.
Finally, compounds that show good in vitro efficacy, low cytotoxicity and optimal physico-chemical properties will be tested for in vivo efficacy using established TB infection models.
References:
(1) BERNEY, M. ET AL. (2015) ESSENTIAL ROLE OF METHIONINE AND S-ADENOSYLMETHIONINE IN THE AUTARKIC LIFESTYLE OF MYCOBACTERIUM TUBERCULOSIS. PNAS
(2) HASENOEHRL, E.J. ET AL. (2019) DERAILING THE ASPARTATE PATHWAY OF MYCOBACTERIUM TUBERCULOSIS TO ERADICATE PERSISTENT INFECTION. NATURE COMMUN.