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Mycobacterium abscessus (M .  abscessus) , a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of  M .  abscessus  pulmonary infections are poorly effective due to the intrinsic resistance of this bacteria against a broad range of antibiotics including anti-tuberculosis agents. Consequently, the number of drugs that are efficient against  M .  abscessus  remains limited. In this context, 19 oxadiazolone ( OX ) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of  M .  abscessus . Several  OXs  impair extracellular  M .  abscessus  growth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibiting  M .  abscessus  growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of  M .  abscessus  growth,  i . e ., compound  iB p PPOX ,  via  activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in  M .  abscessus  lipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target of  iB p PPOX . This study clearly emphasizes the potential of the  OX  derivatives to inhibit the extracellular and/or intracellular growth of  M .  abscessus  by targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.

Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus