Dissecting The Antibacterial Activity Of Oxadiazolone-Core Derivatives Againstmycobacterium Abscessus

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 ofM.abscessuspulmonary 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 againstM.abscessusremains limited. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants ofM.abscessus. SeveralOXsimpair extracellularM.abscessusgrowth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibitingM.abscessusgrowth 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 ofM.abscessusgrowth,i.e., compoundiBpPPOX,viaactivity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved inM.abscessuslipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target ofiBpPPOX. This study clearly emphasizes the potential of theOXderivatives to inhibit the extracellular and/or intracellular growth ofM.abscessusby targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.