Transcriptional adaptation of Mycobacterium ulcerans in an original mouse model: New insights into the regulation of mycolactone

Abstract

Mycobacterium ulcerans is the causal agent of Buruli ulcer, a chronic infectious disease and the third most common mycobacterial disease worldwide. Without early treatment, M. ulcerans provokes massive skin ulcers, caused by the mycolactone toxin, its main virulence factor. However, spontaneous healing may occur in Buruli ulcer patients several months or years after the disease onset. We have shown, in an original mouse model, that bacterial load remains high and viable in spontaneously healed tissues, with a switch of M. ulcerans to low levels of mycolactone production, adapting its strategy to survive in such a hostile environment. This original model offers the possibility to investigate the regulation of mycolactone production, by using an RNA-seq strategy to study bacterial adaptation during mouse infection. Pathway analysis and characterization of the tissue environment showed that the bacillus adapted to its new environment by modifying its metabolic activity and switching nutrient sources. Thus, M. ulcerans ensures its survival in healing tissues by reducing its secondary metabolism, leading to an inhibition of mycolactone synthesis. These findings shed new light on mycolactone regulation and pave the way for new therapeutic strategies.

Repurposing of statins for Buruli Ulcer treatment: antimicrobial activity against Mycobacterium ulcerans

“…It remains currently unclear whether the cholesterol-lowering effect of statins could decrease mycolactone passive diffusion by preventing membrane remodeling. Cholesterol also contributes to the pool of metabolic building blocks, including acetyl-CoA, propionyl-CoA, succinyl-CoA, and pyruvate (Yam et al, 2009;Yang et al, 2009;Hu et al, 2010;Nesbitt et al, 2010;VanderVen et al, 2015), that are essential for mycolactone synthesis (Stinear et al, 2007;Robbe-Saule et al, 2021), raising the hypothesis that statins could affect toxin production. Moreover, these cholesterol-derived substrates accumulate within the caseous necrotic center of tuberculous granulomata, creating a permissive fatty acid-rich environment for M. tuberculosis persistence (Brzostek et al, 2009;Caceres et al, 2009;Ehrt and Rhee, 2013;Lovewell et al, 2016).…”

Induced Synthesis of Mycolactone Restores the Pathogenesis of Mycobacterium ulcerans In Vitro and In Vivo

“…Transcriptional analysis of the mycolactone synthesis genes during this time demonstrates no differences in mRNA levels compared to the ulcerative stage of infection. These observations indicate that Mul must adapt to its metabolic levels to survive spontaneous healing, thus lowering mycolactone production posttranscriptionally ( 55 ). If mycolactone levels in vivo are controlled by a posttranscriptional mechanism relating to bacteria metabolism, the induced expression of mycolactone under a tetracycline-constitutive promoter will provide valuable and accurate insights into the role of mycolactone during bacterial infection.…”

Genome-wide screening identified SEC61A1 as an essential factor for mycolactone-dependent apoptosis in human premonocytic THP-1 cells

“…Several approaches have been proposed to inhibit mycolactone activity, e . g ., the use of IgG antibody against mycolactone [ 57 , 58 ], the inhibition of the mycolactone synthesis pathway with substrates (malonyl-CoA, methyl malonyl-CoA) [ 59 ] and the attenuation of cytotoxicity with antioxidants [ 48 , 49 ]. At present there is no effective drug to reduce the toxicity of mycolactone, and further drug screening and analysis of the biological activity of mycolactone will be required to develop novel therapeutic modalities to inhibit mycolactone-induced ulceration.…”