Abstract
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 iBpPPOX, 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 iBpPPOX. 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.
Highlights
Non-tuberculous mycobacteria (NTM) are naturally-occurring bacterial species mostly found in soil and water that do not cause tuberculosis or leprosy [1]
We recently investigated the antibacterial activities of 19 oxadiazolonecore (OX) derivatives (Fig 1) against three pathogenic slow-growing mycobacteria: M. marinum, M. bovis BCG as well as M. tuberculosis H37Rv the etiologic agent of tuberculosis [12]
We have reported that the MmPPOX compound was able to prevent intracytoplasmic lipid inclusion (ILI) catabolism in vivo in M. bovis BCG infected murine bone-marrow-derived macrophages [47,48,49]; as well as in vitro under carbon excess and nitrogen-deprived conditions allowing ILI biosynthesis and hydrolysis in M. abscessus [50]
Summary
Non-tuberculous mycobacteria (NTM) are naturally-occurring bacterial species mostly found in soil and water that do not cause tuberculosis or leprosy [1]. OX derivatives susceptibilities to Mycobacterium abscesus (https://www.vaincrelamuco.org/) (project nRF20160501651). Proteomics analyses were supported by the Institut Paoli-Calmettes and the Centre de Recherche en Cancerologie de Marseille. Proteomic analyses were done using the mass spectrometry facility of Marseille Proteomics (marseille-proteomique.univ-amu.fr) supported by IBISA (Infrastructures Biologie Santeet Agronomie), the Canceropole PACA, the ProvenceAlpes-Cote d’Azur Region, the Institut PaoliCalmettes, and Fonds Europeen de Developpement Regional (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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