Building Optimal Three-Drug Combination Chemotherapy Regimens To Eradicate Mycobacterium tuberculosis in Its...

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Mycobacterium tuberculosis (M. tuberculosis) metabolic state critically influences treatment outcomes.
• Optimizing tuberculosis therapy requires understanding antimicrobial effects across different M. tuberculosis growth phases.
• A model-informed strategy accelerates the discovery of effective drug combinations.

Purpose of the Study:

• To quantify the efficacy of antimicrobial combinations against M. tuberculosis in its acid-phase metabolic state.
• To evaluate single, two-, and three-drug regimens including pretomanid, moxifloxacin, and bedaquiline.
• To predict and compare bacterial population decline using modeling and time-kill studies.

Main Methods:

• Time-kill studies were conducted using various concentrations of pretomanid, moxifloxacin, and bedaquiline against M. tuberculosis.
• A nonparametric modeling approach was employed to analyze drug interactions.
• Simulated bacterial population declines were compared with observed declines from two- and three-drug regimens.

Main Results:

• The combination of pretomanid and moxifloxacin eradicated M. tuberculosis in the acid growth phase at human-equivalent concentrations.
• This two-drug regimen prevented the emergence of less susceptible M. tuberculosis isolates.
• Adding bedaquiline as a third drug significantly shortened the time to bacterial suppression by 8 days compared to the two-drug regimen.

Conclusions:

• Pretomanid and moxifloxacin combination therapy is effective against M. tuberculosis in its acid growth phase.
• Adding bedaquiline enhances the speed of bacterial suppression, offering a faster therapeutic option.
• These findings support optimized combination therapies for tuberculosis treatment.