Anti-virulence therapies for tuberculosis
Historically, TB drug development has focused on bactericidal agents. Anti-virulence strategies that target key bacterial factors do not affect bacillary survival, thereby avoiding the selection pressure that leads to development of antimicrobial resistance (AMR). Combining this approach with traditional antimicrobial chemotherapy presents a promising avenue for TB therapy, with the potential to mitigate AMR. However, a major challenge in applying this strategy to treatment of M. tuberculosis is its complex array of secreted and cell wall-associated virulence factors, which frequently have overlapping functions.
The unique hydrophobic cell envelope of M. tuberculosis, rich in mycolic acids, shields it from host defences and antibiotics while also modulating immune responses, thus promoting bacterial survival in macrophages. Given the crucial role of cell wall lipids in M. tuberculosis survival and immune evasion, we hypothesize that disruption of lipid biogenesis could result in both antimicrobial and immunostimulatory effects. We have previously shown that mycobacterial Biotin Protein Ligase (BPL) activity is crucial for maintaining cell wall integrity, and that targeting BPL disrupts bacillary lipid biosynthesis to impact all lipid-associated virulence factors and thereby overcome many of the challenges to development of effective anti-virulence therapies. Ongoing research to exploit mycobacterial BPL as a drug target could lead to development of new treatments that combine powerful antibacterial effects with immunostimulatory activity to improve clinical outcomes.
Projects
Inhibiting Mycobacterium tuberculosis Biotin Protein Ligase to target bacterial virulence factors: a novel therapeutic strategy. MRC Project Grant, PI Divya Tiwari,
£1,229,706.