The Chemistry and Biology of Mycolactones
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The chemistry and biology of mycolactones Matthias Gehringer and Karl-Heinz Altmann*§ Review Open Access Address: Beilstein J. Org. Chem. 2017, 13, 1596–1660. Department of Chemistry and Applied Biosciences, Institute of doi:10.3762/bjoc.13.159 Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland Received: 30 May 2017 Accepted: 21 July 2017 Email: Published: 11 August 2017 Karl-Heinz Altmann* - [email protected] This article is part of the Thematic Series "Lipids: fatty acids and * Corresponding author derivatives, polyketides and isoprenoids". § Phone: +41-44-6337390; Fax: +41-44-6331369; Guest Editor: J. S. Dickschat Keywords: Buruli ulcer; mode of action; mycolactones; structure–activity © 2017 Gehringer and Altmann; licensee Beilstein-Institut. relationships; target elucidation; total synthesis License and terms: see end of document. Abstract Mycolactones are a group of macrolides excreted by the human pathogen Mycobacterium ulcerans, which exhibit cytotoxic, immunosuppressive and analgesic properties. As the virulence factor of M. ulcerans, mycolactones are central to the pathogenesis of the neglected disease Buruli ulcer, a chronic and debilitating medical condition characterized by necrotic skin ulcers. Due to their complex structure and fascinating biology, mycolactones have inspired various total synthesis endeavors and structure–activity rela- tionship studies. Although this review intends to cover all synthesis efforts in the field, special emphasis is given to the comparison of conceptually different approaches and to the discussion of more recent contributions. Furthermore, a detailed discussion of mo- lecular targets and structure–activity relationships is provided. Review I. Mycolactones and Buruli ulcer Buruli ulcer is a chronic and debilitating disease characterized disease stages might be confused with insect bites, boils, by skin ulcers and necrotic cutaneous lesions. Ulcers typically lipomas or diverse subcutaneous infections [3]. The ulcerative occur at the limbs and can extend to 15% of the skin surface if stage is characterized by massive necrotic tissue destruction. untreated. The disease is caused by the pathogen Mycobac- Lesions are mainly located in the upper and lower limbs (35% terium ulcerans and represents the third most common and 55%, respectively) while only 10% occur at other parts of mycobacterial infection after tuberculosis and leprosy [1-3]. the body [3]. Generally, large numbers of extracellular mycobacteria are observed in all, the early, the pre-ulcerative At its outset Buruli ulcer usually occurs as painless subcuta- and the ulcerative disease stage without being accompanied by neous swellings in the form of nodules, papules, plagues or granuloma formation [5]. The ulcers expand over time and can diffuse edema [4]. Due to their inconspicuous appearance, early spread over the entire extremities. However, ulceration is 1596 Beilstein J. Org. Chem. 2017, 13, 1596–1660. normally not accompanied by pain and fever although those MacCallum later suggested the name Mycobacterium ulcerans symptoms might be present in severe forms. In 5–10% of all [17]. Initial attempts to cultivate the bacterium failed until it cases, M. ulcerans also invades the bone and causes was realized that, in contrast to M. tuberculosis that can be osteomyelitis leading to serious disabilities and severe deformi- grown at 37 °C, M. ulcerans requires temperatures above 25 °C, ties [4,6]. Although Buruli ulcer itself is rarely life threatening, but below 37 °C (ideally 32–33 °C) for growth [16]. This might untreated disease generally results in severe functional and be one of the reasons why M. ulcerans infections in humans are aesthetic squeal [7] and increases the risk for dangerous second- primarily limited to cutaneous tissue. Furthermore, low oxygen ary infections [8]. concentrations were later shown to be beneficial for cultivating this very slow growing mycobacterium [18]. A few years after Buruli ulcer is one of currently 18 neglected tropical diseases their initial characterization, infections with M. ulcerans were (NTDs) according to the WHOs classification and primarily also observed in today’s Democratic Republic of Congo [19] affects children under the age of fifteen. M. ulcerans infections and in Uganda [20-22]. The name Buruli ulcer was suggested in have been reported from at least 33 countries, typically in trop- relation to case reports from Buruli County in Mengo district ical and subtropical regions, and represent a substantial societal (today Nakasongola district) in Uganda [20]. Although Bairns- and economic burden [9]. Although the vast majority of Buruli dale ulcer would be the historically more correct denomination, ulcer cases has been reported for Western sub-Saharan Africa the WHO approved the name Buruli ulcer. (especially from Ivory Coast, Benin, Ghana and the Demo- cratic Republic of the Congo), the pathogen is also endemic in Despite the long known association of Buruli ulcer with riverine South America, the Western Pacific region (incl. Australia) and areas and wetlands [22,23], the natural reservoir of M. ulcerans Asia (e.g., China and Japan). In certain highly endemic regions is still elusive and due to its obscure route of transmission [12], like the Zou department in southern Benin, the prevalence of Buruli ulcer is sometimes referred to as the “mysterious Buruli ulcer can even exceed that of tuberculosis or leprosy disease” [24]. While M. ulcerans is believed to be an environ- [10]. Since 2010, the number of reported Buruli ulcer infec- mental pathogen [25], there is putative evidence that it can also tions worldwide has declined from almost 5000 annual cases to be hosted and transmitted by living organisms such as aquatic approximately 2000 in 2015 [11,12], but the reasons for this de- insects [26], mosquitoes [27], fish and amphibians [28]. crease are unknown [3]. However, these numbers have to be treated with care and numerous cases have to be assumed to Upon infection, M. ulcerans is usually concentrated in a small remain unreported, since only 15 countries regularly report data focus surrounded by a larger necrotic area that contains few to the WHO [3]. In addition, infections might often remain bacteria. Based on this observation, Connor and Lunn specu- unrecognized, due to poor healthcare standards in most of the lated already in 1966 that M. ulcerans might excrete a diffusible affected countries [12]. toxin [21]. In 1974, two reports by Connor and co-workers corroborated this hypothesis by demonstrating that the injection The first suspected case of a M. ulcerans infection was reported of culture filtrates from different M. ulcerans strains into mouse in the early 1860s by Captain James August Grant in his footpads and guinea pig skin caused similar effects as the inocu- accounts of his journey with John Hanning Speke on their quest lation with the living organism [29,30]. These studies also sug- for the source of the White Nile. In his book A walk across gested that the toxin had a molecular mass of around Africa or domestic scenes from my Nile journal [13] a detailed 100,000 Da and was moderately heat stable. Four years later, in description of his condition is given that reflects the symptoms 1978, Krieg and co-workers proposed the toxin to be a phos- of the edematous form of Buruli ulcer as it is occurring in pholipoprotein–polysaccharide complex, based on studies in- Central and Western Africa [14]. The first clinical description vestigating the stability of M. ulcerans extracts towards differ- of Buruli ulcer was provided in 1897 by the medical missionary ent chemicals and enzymes [31]. The true nature of the toxin, Sir Ruskin Albert Cook in Kampala (Uganda) [15]. More than however, remained elusive until 1998, when Small and 50 years later, a seminal report by MacCallumn and co-workers co-workers identified a polyketide isolated from acetone- from Bairnsdale hospital (Victoria, Australia) described six soluble M. ulcerans lipid extracts as the key virulence factor patients from rural riverine areas suffering from an unknown [32,33]. The initial characterization of the toxin relied on the ulcerative infection [16]. A “mycobacterium hitherto separation of extract components by thin layer chromatography unrecorded and pathogenic to man” was found in the patients’ (TLC) and the biological characterization of the individual lesions. Biopsy and microscopic analysis revealed a unique bands, a process that revealed a light yellow UV-active compo- histopathological pattern in all patients that distinctly differed nent to possess the highest cytopathogenic activity. Further from tuberculosis. However, the germ gave the typical acid-fast purification of this material by reversed-phase HPLC and subse- stain common to all mycobacteria. As reported by Fenner et al., quent characterization by high-resolution mass spectrometry 1597 Beilstein J. Org. Chem. 2017, 13, 1596–1660. and two-dimensional NMR spectroscopy unveiled a 12-mem- Indeed, this presumption was later proven to be true by the bered macrolactone substituted with two polyketide-derived (attempted) targeted total synthesis of each isomer; as part of side chains (Figure 1). Based on its mycobacterial origin and its this work, mycolactones A and B were shown to rapidly equili- chemical structure, this compound was named mycolactone. It brate under standard laboratory conditions [37]. The prevalence is worth noting that mycolactone represented the first polyke- of the Z-Δ4’,5’