Production of avermectins: Biotechnologies and organic synthesis

Abstract

The proposed review analyzes the results of research on various aspects of improving the technology of obtaining avermectins, the 16-membered macrocyclic lactones which have a wide spectrum of antiparasitic action with a high therapeutic index and harmlessness for mammals (W.C. Campbell, 2012). According to published data, the unique ability of avermectins to suppress the development of insects, nematodes and ticks is associated with the ability to block the transmission of nerve impulses in the neuromuscular synapse. The essence of this mechanism of action, leading to paralysis and death of parasites, is to stimulate the release of chlorine ions, depolarization of the cell membrane and pathological disorders of its functions (A.J. Wolstenholme et al., 2016). Of the known 8 components (A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b) of the avermectin complex produced by the microorganism Streptomyces avermitilis, the avermectin B1 is the most active against parasite pathogens (S. Omura, 2002; W.C. Campbell, 2012). Therefore, the main studies on the production of avermectins are associated with the selection of highly productive strains which predominantly synthesize avermectins B1 (S.S. Ki et al., 2005; H. Gao et al., 2010; W. Liu et al., 2015; L. Meng et al., 2016), and the preparation of semi-synthetic analogs of avermectins B1 with improved physicochemical and pharmacological properties (J. Vercruysse et al., 2001; A. Awasthi et al., 2012). Attempts to develop a technology for the complete chemical synthesis of avermectins have not yet yielded significant results due to the low yield of the target product and the complexity of the synthesis scheme (S. Yamashita et al., 2016). Considerable attention has been paid to the biochemical aspects of the diversity of 16-membered macrocyclic lactones and their producers, as well as to semisynthetic analogues, and prospects for searching for new highly efficient and environmentally friendly semisynthetic analogues of avermectin B1 have been defined. Main streams of researches on genetics, biochemistry and physiology of the producer of avermectins, ways of regulated culture of S. avermitilis strains and biosynthesis of required components of avermectin complex are discussed (S. Kitani et al., 2009; J. Guo et al., 2018). The data on the problem of emerging resistance in some species of parasites to long-used avermectin-containing drugs are analyzed. This phenomenon is shown to have a multifactor nature, including mutation of genes determining GluCl subunits and increased P-glycoprotein expression (J.H. Gill et al, 1998; R.K.Prichard, 2007; F.D. Guerrero et al., 2012; P.C. Pohl et al., 2014; P. Godoy et al, 2016). For the successful control of nematodes, insects and mites of agricultural, sanitary and medical importance, it seems appropriate to create drugs based on natural avermectins and their new semi-synthetic derivatives, for example, 5-O-succinylavermectin B1 and C2017 compounds.