Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls

Abstract

Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. One promising alternative for the discovery of novel potent analgesics is to take inspiration from Mother Nature; in this context, the detailed investigation of the intriguing analgesia implemented in Buruli ulcer, an infectious disease caused by the bacterium Mycobacterium ulcerans and characterized by painless ulcerative lesions, seems particularly promising. More precisely, in this disease, the painless skin ulcers are caused by mycolactone, a polyketide lactone exotoxin. In fact, mycolactone exerts a wide range of effects on the host, besides being responsible for analgesia, as it has been shown notably to modulate the immune response or to provoke apoptosis. Several cellular mechanisms and different targets have been proposed to account for the analgesic effect of the toxin, such as nerve degeneration, the inhibition of inflammatory mediators and the activation of angiotensin II receptor 2. In this review, we discuss the current knowledge in the field, highlighting possible controversies. We first discuss the different pain-mimicking experimental models that were used to study the effect of mycolactone. We then detail the different variants of mycolactone that were used in such models. Overall, based on the results and the discussions, we conclude that the development of mycolactone-derived molecules can represent very promising perspectives for new analgesic drugs, which could be effective for specific pain indications.

The Neuropeptide-Related HERC5/TAC1 Interactions May Be Associated with the Dysregulation of lncRNA GAS5 Expression in Gestational Diabetes Mellitus Exosomes

“…However, SP has been shown to play a role in preventing complications in T2DM by reducing IR in target tissues through immunomodulation [ 68 ]. Furthermore, SP can act on inflammatory cells, leading to the release of inflammatory mediators [ 69 ]. Inflammation is an important pathological mechanism in GDM [ 70 ].…”

The Angiotensin AT2Receptor: From a Binding Site to a Novel Therapeutic Target

“…In an entirely different scenario, the mycobacterial polyketide mycolactone activated neuronal AT 2 Rs, leading to potassium-dependent hyperpolarization that induced analgesic effects (Marion et al, 2014;Song et al, 2017). This is, apparently, the underlying mechanism of how the severe Buruli ulcers induced by Mycobacterium ulcerans in humans are painless, a mechanism with translational potential (Babonneau et al, 2019;Reynaert et al, 2019).…”

Density Functional Theory-Based Studies Predict Carbon Nanotubes as Effective Mycolactone Inhibitors

“…Because mycolactone is lipophilic, it is thought to passively penetrate cell membranes and bind to crucial proteins involved in platelet and mast cell exocytosis, hence slowing wound healing [ 6 , 7 ]. According to recent research, mycolactone exerts a pleiotropic effect and disrupts basic cellular processes such as cell attachment, signaling pathways, cell proliferation, cell death, and inflammation [ 8 ]. This accounts for the painless, slow-healing ulcer lesions associated with BU.…”

“…However, significant progress has been made in understanding the multifaceted role of mycolactone in host colonization. Some of these roles include an immunomodulatory effect, targeting the Sec61 channel and facilitating immunological escape [ 8 ], and an analgesic effect, targeting AT2R receptors and accounting for painlessness in individuals with early BU lesions [ 3 ]. Despite this progress, there remain some challenges since generated neutralizing antibodies have the drawback of being produced from hybridomas [ 9 ].…”