Fatty acid-dependent cidality in Mycobacterium avium and Mycobacterium abscessus: intracellular acidification by itaconic acid

Non-tuberculous mycobacterial (NTM) lung disease is now recognized as a chronic condition with considerable morbidity and mortality with incidence rising globally. This is concerning as these infections are often mis- or undiagnosed and currently available treatment regimens have lengthy (>1 year) treatment courses with variable to poor success rates. Identification of vulnerable targets and pathways in NTM pathogens is urgently needed to develop improved therapeutics. Itaconic acid (ITA), a macrophage-produced metabolite with immunomodulatory and antibacterial activity, inhibits growth of mycobacteria and here, we provide further important insights into the activity and mechanism of action for ITA. ITA displayed robust bactericidal activity against the prominent NTM pathogens Mycobacterium avium ( M. avium ) and M. abscessus in a pH- and fatty acid-dependent manner, conditions that these bacteria experience within phagosomes during infection. Using a genetically encoded intrabacterial pH reporter, we demonstrate that ITA induces intracellular acidification in a pH-dependent manner. This work reveals that disruption of NTM pH homeostasis is a vulnerability in these difficult-to-treat pathogens which could be exploited for therapeutic benefit.