Toward a Bactericidal Oral Drug Combination for the Treatment of <i>Mycobacterium abscessus</i> Lung Disease

Treatment of <i>Mycobacterium abscessus</i> 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 <i>M. abscessus</i> 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.