Strain diversity drives heterogeneous responses to tuberculosis combination therapy

Area of Science:

• Microbiology and Infectious Diseases
• Pharmacology and Drug Discovery

Background:

• Strain diversity in Mycobacterium tuberculosis (Mtb) influences clinical outcomes.
• Understanding drug susceptibility phenotypes across diverse Mtb clinical isolates is crucial but limited.
• Phylogenetic diversity of Mtb strains correlates with varying disease progression and treatment responses.

Purpose of the Study:

• To identify distinct drug response patterns in phylogenetically diverse Mtb clinical isolates.
• To evaluate the efficacy of single-drug, two-drug, and three-drug combinations against Mtb under different metabolic conditions.
• To inform preclinical Mtb regimen design by considering strain-specific drug responses.

Main Methods:

• Selected 13 diverse Mtb clinical isolates plus one reference strain (Erdman ATCC-35801).
• Tested 65 drug combinations (10 single drugs, 45 pairs, 20 three-way combinations) in standard and cholesterol-rich media.
• Assessed drug potency and synergy across strains and metabolic conditions.

Main Results:

• Mtb clinical strains exhibited a wide spectrum of drug response phenotypes.
• Optimal drug pairs varied significantly based on Mtb strain and metabolic environment.
• Reduced sensitivity to single drugs correlated with reduced sensitivity to combination treatments.
• Drug combination potency variation was primarily driven by closely related strains, not disparate lineages.
• Differential effectiveness of drug combinations was observed against Mtb in different carbon sources.

Conclusions:

• Preclinical Mtb regimen design should prioritize strain selection based on drug response phenotypes, not solely genetic diversity.
• The efficacy of Mtb drug combinations is strain- and condition-dependent.
• Optimizing drug combinations requires considering infecting strain, metabolic niche, and specific drug response metrics.