Inhibitors of the oxidative phosphorylation pathway and their interaction with antibiotics in Mycobacteroides abscessus

Abstract

Mycobacteroides abscessus belongs to the family Mycobacteriaceae, along with highly pathogenic species Mycobacterium tuberculosis and Mycobacterium leprae, causative agents of tuberculosis and leprosy respectively. Since nontuberculous mycobacteria (NTM) are ubiquitous in the environment, human exposure is common, though severe disease is often limited to susceptible individuals such as the immunocompromised and those with underlying lung conditions. The rapidly growing M. abscessus is the most frequently isolated species from patients with NTM disease in Singapore. Due to its high levels of intrinsic drug resistance and increasing incidence of inducible resistance, treatment is largely ineffective or associated with relapse.

The drug development pipeline for NTMs such as M. abscessus has provided some limited but promising results. Of note, the discovery of bedaquiline used in the treatment of M. tuberculosis established a new target for the development of antimicrobial compounds – the oxidative phosphorylation pathway. Its effectiveness in NTMs is yet to be established, with several studies publishing conflicting results of their in vivo studies. Thus, it can only be used on a compassionate basis after standard treatment options have failed.

To incorporate these new drugs into treatment regimen, it is important to further our understanding of the interaction between new drugs and classical antibiotics. In this study, we noted that inhibitors of the oxidative phosphorylation pathway used in combination with different classical antibiotics against M. abscessus shows a wide variance in effectiveness, working synergistically with some but antagonistically with others. In exploring the underlying mechanisms, we discovered that some classical antibiotics, in particular the β-lactams, rely on upregulation of bacterial metabolism to cause cell death. Thus, they are antagonistic with metabolic inhibitors such as the inhibitors of the oxidative phosphorylation pathway. However, there is yet more to be discovered in establishing our understanding of the mechanisms of interaction between the drug classes.