Abstract
Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria. Of particular importance is bedaquiline (Sirturo), which kills mycobacteria by inhibiting the F1F0 ATP synthase. Other components of the electron transport chain such as the NADH dehydrogenases (NDH-2 and NdhA) and the terminal respiratory oxidase bc1:aa3 are also susceptible to chemical inhibition. Because antituberculosis drugs are prescribed as part of combination therapies, the interaction between novel drugs targeting energy metabolism and classical first and second line antibiotics must be considered to maximize treatment efficiency. Here, we show that subinhibitory concentration of drugs targeting the F1F0 ATP synthase and the cytochrome bc1:aa3, as well as energy uncouplers, interfere with the bactericidal potency of isoniazid and moxifloxacin. Isoniazid- and moxifloxacin-induced mycobacterial death correlated with a transient increase in intracellular ATP that was dissipated by co-incubation with energy metabolism inhibitors. Although oxidative phosphorylation is a promising target space for drug development, a better understanding of the link between energy metabolism and antibiotic-induced mycobacterial death is essential to develop potent drug combinations for the treatment of tuberculosis.
Highlights
Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria
Isoniazid- and moxifloxacininduced mycobacterial death correlated with a transient increase in intracellular ATP that was dissipated by co-incubation with energy metabolism inhibitors
We chose to study the interaction between inhibitors of energy metabolism with isoniazid and moxifloxacin, which are key drugs for the management of pan-susceptible and Multidrug resistant (MDR) tuberculosis, respectively
Summary
The first 2 months [1]. Despite being selected from a limited pool of antituberculosis drugs more than 50 years ago, this combination remains very effective with a relapse rate of less than 2% at 2 years after treatment [2]. In the absence of potent companion drugs, the emergence of resistance to bedaquiline and delamanid has been observed less than 3 years after market approval [7, 8]. These two drugs are interesting because they represent novel classes of antibiotics that inhibit energy metabolism in mycobacteria. Given the rate at which drugs targeting energy metabolism are discovered, the investigation of their interaction with classical first- and second-line anti-TB drugs becomes essential This is important in light of an emerging model that links antibiotic-induced death in bacteria to a pathway involving dysregulation of central metabolism and energetic pathways [21, 22]. This study highlights the complexity of antibiotic-induced death in mycobacteria and advocates for a better understanding of this fundamental aspect to aid the development of rational drug combination for the treatment of tuberculosis
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