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Toward a Bactericidal Oral Drug Combination for the Treatment of Mycobacterium abscessus Lung Disease
Jickky Palmae Sarathy1, Min Xie1, Chui Fann Wong1
1Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
Abstract:
Treatment of Mycobacterium abscessus lung disease relies on underperforming drug combinations and includes parenteral, poorly tolerated, and bacteriostatic antibiotics. We posit that safe, oral, and bactericidal regimens are needed to improve cure rates and shorten treatment. Here, we combined oral representatives of three well-tolerated bactericidal drug classes, the β-lactam tebipenem (together with the β-lactamase inhibitor avibactam), the fluoroquinolone moxifloxacin, and the rifamycin rifabutin, and profiled the combination in vitro and in vivo. The combination potentiated bactericidal activity of its components against replicating M. abscessus and retained bactericidal activity against the nonreplicating, drug-tolerant form of the bacterium residing in surrogate caseum. When combined, the drugs retained the ability to induce lethal secondary effects associated with the β-lactam and fluoroquinolone, including cell wall and DNA damage, increased metabolism, and generation of reactive oxygen species. Thus, the triple-drug combination appears to exert two lethal punches while suppressing bacterial reprogramming to counter the drug-induced stresses, providing a plausible rationale for the enhanced kill effect. Addition of a bacteriostatic agent resulted in drug-specific patterns of interactions with regards to bactericidal activity reflected by the lethal secondary effects. The triple-drug combination also exerted a pronounced postantibiotic effect and reduced emergence of spontaneous resistant mutants. Collectively, this work provides a combination prototype for optimization and a profiling workflow that may be useful for the development of sterilizing regimens.
Insights
New oral antibiotics show promise for treating lung disease caused by Mycobacterium abscessus. This triple-drug combination is bactericidal against replicating and dormant bacteria, offering a potential new treatment strategy.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Current Mycobacterium abscessus lung disease treatments use ineffective drug combinations.
- Parenteral, poorly tolerated, and bacteriostatic antibiotics limit treatment efficacy.
- Need exists for safe, oral, bactericidal regimens to improve cure rates and shorten treatment duration.
Purpose of the Study:
- To evaluate a novel triple-drug combination of oral bactericidal agents against Mycobacterium abscessus.
- To assess the combination's efficacy against both replicating and non-replicating M. abscessus.
- To investigate the mechanisms underlying the combination's enhanced bactericidal activity.
Main Methods:
- In vitro and in vivo profiling of a combination including tebipenem-avibactam, moxifloxacin, and rifabutin.
- Assessment of bactericidal activity against replicating and non-replicating M. abscessus.
- Evaluation of drug-induced lethal secondary effects and postantibiotic effects.
Main Results:
- The triple-drug combination demonstrated potentiated bactericidal activity against replicating M. abscessus.
- The combination retained efficacy against non-replicating, drug-tolerant M. abscessus.
- Drugs maintained lethal secondary effects (cell wall/DNA damage, ROS generation), suggesting a dual-action mechanism.
- The combination reduced the emergence of resistant mutants and showed a pronounced postantibiotic effect.
Conclusions:
- This triple-drug combination represents a promising prototype for developing improved Mycobacterium abscessus lung disease treatments.
- The combination's ability to target both replicating and dormant bacteria and its favorable pharmacokinetic profile warrant further investigation.
- The developed profiling workflow may aid in creating sterilizing regimens for challenging bacterial infections.
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