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Synthesis and Anti-mycobacterial Activity of Novel Medium-chain β-Lactone Derivatives: A Multi-Target Strategy to combat Mycobacterium abscessus and other Pathogenic Mycobacteria

ABSTRACT: Targeting the enzymes involved in mycobacterial lipid metabolism; which are mainly serine and cysteine enzymes (i.e., (Ser/Cys)-based enzymes; has emerged as a promising strategy to combat not only M. tuberculosis, but also other chronic non-tuberculous mycobacterial infections like those caused by M. marinum or M. abscessus. Among the known inhibitors of such mycobacterial enzymes, β-lactones represent promising candidates for the development of new derivatives that target lipid-processing enzymes critical for mycobacterial growth and survival. In this context, a new set of 38 lipophilic β lactone derivatives have been synthesized and tested for their anti-mycobacterial activities against the three aforementioned pathogenic mycobacteria. Remarkably, the determined MIC revealed that some VM β-lactones were able to inhibit M. abscessus growth in vitro in culture broth medium and/or inside infected macrophages. In addition, using a competitive activity-based protein profiling approach, the potential target enzymes of VM043, the most active inhibitor of extracellular bacterial growth, were further identified; thus, confirming the multi-target nature of this family of molecules.

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ORGANISM(S): Mycobacteroides Abscessus Subsp. Abscessus Mycobacterium Tuberculosis Bacteria

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Dr CAVALIER Jean-François

PROVIDER: PXD057836 | Pride | 2025-04-23

REPOSITORIES: Pride

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Project description:Members of the Mycobacterium (M.) abscessus complex (MABC) are rapidly growing mycobacteria showing smooth and/or rough colony morphotype. While not as virulent as M. tuberculosis, they can cause soft tissue infection and fatal pulmonary disease, especially in patients with cystic fibrosis. Diagnosing MABC pulmonary disease is challenging since the isolation of M. abscessus from respiratory samples is in itself not diagnostic and the clinical features are often non-specific. Immunologic assays, which could aid in the understanding and diagnosis of the disease, are not available. In this study eight rough and six smooth colony morphotype isolates were collected from seven clinical MABC strains and the M. abscessus reference strain ATCC19977, as six strains showed both morphotypes simultaneously and two strains only showed a rough morphotype. Clinical isolates were submitted to whole genome sequencing. Quantitative proteomic analysis was performed on bacterial lysates and the culture supernatant of all 14 isolates. Supernatant proteins present in all isolates were compared in a BLAST search against other clinically significant mycobacterial species to determine species-specific proteins of MABC. In silico B- and T-cell epitope prediction was performed for species-specific proteins. All clinical strains were found to be M. abscessus ssp. abscessus. Six of seven rough colony clinical isolates contained genetic changes in the MAB_4099c gene, which is a likely genetic basis for the rough morphotype. Proteomic analysis detected 3 137 different proteins in total of which 79 proteins were found in the culture supernatants of all isolates. BLAST analyses of these 79 proteins identified 12 of those exclusively encoded by all members of MABC plus M. immunogenum. In silico prediction of epitopes predicted B- and T-cell epitopes in all these 12 species-specific proteins, rendering them promising candidates for future studies on immune pathogenesis and immune diagnostic tools for MABC disease.

Project description:Tuberculosis (TB) which is one of the deadliest infectious disease worldwide, is caused by the inhalation of the pathogenic bacteria Mycobacterium tuberculosis. Since many years now, the emergence of multiple (MDR), extensively (XDR) and totally (TDR) drug resistant strains amplifies the incidences of TB resulting in failure of treatment and death. However, no new TB drug classes have been developed or approved for drug susceptible TB since the current 6-month four-drug combination was introduced in the 1970s. Most of the promising new molecules in development are either repurposed drug compounds or new derivatives of known anti-mycobacterial drugs that mainly target the bacteria cell wall biosynthesis. It is now acknowledged that microbial lipolytic enzymes are involved in bacterial growth, cell wall biosynthesis, carbon sources management and virulence during infections by M. tuberculosis. Although no drug is reported to target specifically enzymes involved in mycobacterial intracellular lipid metabolism; our results have clearly shown that mycobacterial enzymes can be potential therapeutic targets. Consequently, specific inhibitors of such enzymes might turn out to be valuable anti-tuberculous agents. We previously reported that the Cyclophostin & Cyclipostins (CyC) analogs are a new family of potent antimycobacterial molecules which react specifically and covalently with (Ser/Cys)-based enzymes. Competitive ABPP approach with CyC17-pretreated M. tb lysate and the ActivX Desthiobiotin-FP activity-based probe (ABP) allowed identifying 23 distinct proteins as potential targets of this inhibitor, that were all (Ser/Cys)-based enzymes, most of them participating in M. tb lipid metabolism and cell wall biosynthesis. However, this approach for target identification in cell lysates is mostly indirect with the risk of false positive hits, and cannot be applied in vivo for various technical reasons, the main one being the need for a large number of compounds and cells. To overcome these issues, we report here the synthesis of new CyC alkyne-containing inhibitors (i.e., CyCyne) analogous to CyC17, and their use for the direct fishing of target proteins in living M. tb via bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) strategy. In particular, we further explore and validate, through a combination of biochemical and structural approaches, the specificity of inhibition of the HsaD activity by the CyC analogs.

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Synthesis and Anti-mycobacterial Activity of Novel Medium-chain β-Lactone Derivatives: A Multi-Target Strategy to combat Mycobacterium abscessus and other Pathogenic Mycobacteria

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