Mycolactone as Analgesic: Subcutaneous Bioavailability Parameters

Abstract

Mycobacterium ulcerans is the bacillus responsible for Buruli ulcer, an infectious disease and the third most important mycobacterial disease worldwide, after tuberculosis and leprosy. M. ulcerans infection is a type of panniculitis beginning mostly with a nodule or an oedema, which can progress to large ulcerative lesions. The lesions are caused by mycolactone, the polyketide toxin of M. ulcerans . Mycolactone plays a central role for host colonization as it has immunomodulatory and analgesic effects. On one hand, mycolactone induces analgesia by targeting type-2 angiotensin II receptors (AT 2 R), causing cellular hyperpolarization and neuron desensitization. Indeed, a single subcutaneous injection of mycolactone into the mouse footpad induces a long-lasting hypoesthesia up to 48 h. It was suggested that the long-lasting hypoesthesia may result from the persistence of a significant amount of mycolactone locally following its injection, which could be probably due to its slow elimination from tissues. To verify this hypothesis, we investigated the correlation between hypoesthesia and mycolactone bioavailability directly at the tissue level. Various quantities of mycolactone were then injected in mouse tissue and hypoesthesia was recorded with nociception assays over a period of 48 h. The hypoesthesia was maximal 6 h after the injection of 4 μg mycolactone. The basal state was reached 48 h after injection, which demonstrated the absence of nerve damage. Surprisingly, mycolactone levels decreased strongly during the first hours with a reduction of 70 and 90% after 4 and 10 h, respectively. Also, mycolactone did not diffuse in neighboring skin tissue and only poorly into the bloodstream upon direct injection. Nevertheless, the remaining amount was sufficient to induce hypoesthesia during 24 h. Our results thus demonstrate that intact mycolactone is rapidly eliminated and that very small amounts of mycolactone are sufficient to induce hypoesthesia. Taken together, our study points out that mycolactone ought to be considered as a promising analgesic.

Development of an ELISA for the quantification of mycolactone, the cytotoxic macrolide toxin of Mycobacterium ulcerans

“…For BU, mycolactone makes an ideal antigen for specific immunodiagnosis given its uniqueness to the mycolactone-producing mycobacteria (MPM). Also, since the levels of mycolactone in tissues are reported to decline during specific treatment [15,16], an assay quantifying mycolactone in BU lesions would be useful in monitoring treatment efficacy.…”

“…Mycolactone represents an ideal target for such an assay, since it seems to be unique to M. ulcerans. A mycolactone-specific assay may also be highly suitable for monitoring treatment efficacy and to diagnose relapses, since mycolactone levels in the affected tissue decline during successful specific therapy [15,16].…”

The signal peptide as a new target for drug design

“…A pharmacokinetic evaluation of mycolactone as a subcutaneous analgesic was recently reported. 55 The authors found that in mice the analgesic effects of mycolactone were dependent on type-2 angiotensin II receptors (AT 2 R) and not related to its previously reported suppression of inflammation. This observation is consistent with the expectation that mycolactone inhibits translocation of the angiotensin precursor protein, angiotensinogen, which is expressed with a 33-residue SP on the N-terminus of its preprotein.…”

Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls

“…Notably, drugs known to activate potassium channels display antinociceptive properties [67] as they induce hyperpolarization, thus decreasing neuron sensitization. The sustained hyperpolarization induced in sensory neurons was proposed to mediate the analgesic properties of mycolactone, in response to a noxious thermal stimulus ([52] (tail-flick adapted test), [53] (Hargreaves plantar test), [68]). In support of this result, hypoesthesia was reported to be dependent on the expression of AT2R, as the genetic knockout of this gene resulted in the restoration of a normal latency period for the sensing of thermal pain in mice [52].…”

“…Indeed, mycolactone, the toxin produced by M. ulcerans , is responsible for the extensive ulcerative skin lesions observed in patients suffering from BU [46,47,48] but also for the painless character of the lesions it causes, at least at early stages of the disease [49,50]. In mice models, mycolactone induces hypoesthesia with an extremely long-lasting effect [51,52,53]. Using chemical synthesis approaches of mycolactone, but also various cellular and in vivo models, several molecular targets have been proposed for mycolactone that would account for its analgesic properties (Figure 1), but their relative contributions to the different effects of mycolactone remain controversial.…”