NAISS
SUPR
NAISS Projects
SUPR
Cryo electron tomography data processing and virtual docking for potential drug targets from Mycobacterium tuberculosis
Dnr:

NAISS 2026/4-757

Type:

NAISS Small

Principal Investigator:

Irwin Selvam

Affiliation:

Stockholms universitet

Start Date:

2026-06-01

End Date:

2027-06-01

Primary Classification:

10601: Structural Biology

Webpage:

Allocation

Abstract

Mycobacterium tuberculosis (Mtb) is the primary causative agent of tuberculosis (TB) in humans and was responsible for 1.23 million deaths in 2024. This places TB as the leading cause of death due to a single infectious agent worldwide. The emergence and spread of drug-resistant strains of Mtb have complicated treatment and are threatening the progress made thus far in controlling TB. As such, there is an urgent need for new therapeutics, the development of which is only possible with a thorough understanding of the biology of Mtb. The Högbom laboratory utilizes a range of structural biology techniques to characterise proteins of interest from Mtb including X-ray crystallography combined with virtual docking and cryo electron tomography (cryo-ET). Computational resources are being applied for in order to complete two independent projects. Firstly, we have recently solved the X-ray crystal of an orphan enzyme from the AccD family of proteins. Other members of the family (in combination with the AccAs and AccE) are involved in leucine catabolism and mycolic acid biosynthesis, both of which are crucial for infection. A fragment screening campaign at the FragMAX facility has provided a starting point for virtual docking against the CBCS in-house compound library in collaboration with Dr Flavio Ballante. The goals of this project are to elucidate the substrate(s) of this enzyme and to develop tool compounds to investigate its function in vivo. Secondly, we aim to determine a subtomogram averaged structure of a protein complex from the model organism M. smegmatis (Msm) in situ with cryo-ET. Currently, there are no structures for this class of complexes determined by cryo-ET. The process by which Mtb aerobically respirates is fundamentally different to that of humans, which opens up the possibility of selectively inhibiting the Mtb electron-transport chain. A preliminary dataset was recently collected by collaborators in Umeå. Processing these series requires HPC resources and will be done in collaboration with Dr Tanvir Shaikh. Once complete, these projects will result in a measurable contribution to the field of mycobacteriology and possibly to the development of next-generation antituberculars.