Increasing the structural coverage of tuberculosis drug targets

Area of Science:

• Structural Biology
• Drug Discovery
• Mycobacteriology

Background:

• High-resolution protein structures are crucial for tuberculosis (TB) drug design but are limited for Mycobacterium tuberculosis (Mtb) targets.
• Existing structural data covers only a small portion of the Mtb proteome, hindering comprehensive drug development efforts.

Purpose of the Study:

• To evaluate an intra-genus "homolog-rescue" strategy to enhance structural information for TB drug discovery.
• To assess the utility of mycobacterial homolog structures as surrogates for Mtb drug design.

Main Methods:

• X-ray crystallography was used to determine structures of Mtb targets and their homologs from other mycobacterial species.
• Active sites of Mtb and non-TB mycobacterial (NTM) enzyme homologs were compared using structural similarity metrics.
• Sequence identity, Cα RMSD, and pharmacophoric property similarity (PSAPF) were employed to quantify active site conservation.

Main Results:

• Only 16 of 179 Mtb targets yielded crystal structures initially.
• Incorporating 1675 homologs from nine other mycobacterial species enabled the solution of 52 additional target structures.
• 41 out of 52 NTM structures shared >55% sequence identity with their Mtb counterparts, indicating conserved active sites.
• The strategy increased effective structural coverage of Mtb targets from 9% to 32% (over three-fold).

Conclusions:

• The "homolog-rescue" strategy effectively increases structural coverage for TB drug discovery.
• Conserved active sites in mycobacterial homologs make them valuable surrogates for Mtb drug design.
• This approach is generalizable to identify drug targets for other diseases.