Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura

Abstract

Nomimicin (1), a new spirotetronate-class polyketide, was isolated from the culture broth of an actinomycete of the genus Actinomadura. Its structure was established by spectroscopic methods, and the absolute configuration was determined by a combination of NOESY experiment, J-based configuration analysis and the modified Mosher method. Nomimicin (1) showed antimicrobial activity against Micrococcus luteus, Candida albincans and Kluyveromyces fragilis. Keywords: Actinomadura; polyketide; spirotetronate INTRODUCTION Microbial secondary metabolites have been the most productive source of small molecules for the development of drugs. 1 Almost a half of the known microbial bioactive compounds are derived from actinomycetes, and specifically Streptomyces accounts for more than 70% of the actinomycete-derived metabolites. 2 Among the nonStreptomyces species, Micromonospora is the leading producer of secondary metabolites, including polyketides, peptides and glycosides, whereas Actinomadura is known as a producer of chemically and biologically unique polyketides such as antitumor enediynes, 3 mannose-binding quinone glycosides with antifungal and anti-HIV activities 4 and anticoccidial polyethers, 5 accounting for up to 350 compounds reported as of 2005. 2 During our continuing investigation on the metabolites from actinomycetes of nonStreptomyces group, 6,7 a new spirotetronate antibiotic of polyketide origin, nomimicin (1, Figure 1), was isolated from the culture extract of Actinomadura sp. TP-A0878. In this paper, we describe the isolation, structural determination and biological properties of 1.

Natural [4 + 2]-Cyclases

“…155–157 A subclass of this family of natural products has drawn particular interest, because the tetronate or tetramate namesake appears to have undergone an intramolecular Diels-Alder reaction with a 1,3-diene to form a cyclohexene ring with a tertiary carbon joint. 12,157 Examples of such spirotetronates and spirotetramates are shown in Figure 6 and include versipelostatin ( 74 ), 158–161 pyrroindomycin ( 75 ), 162–166 chlorothricin ( 76 ), 167–175 kijanimicin ( 77 ), 176–181 the quartromicins ( 78 ), 182–186 the abyssomicins ( 79 ), 187–192 tetrocarcin, 193–198 the lobophorins, 199–205 nomimicin, 206 maklamicin, 207–209 and tetronothiodin. 210–214 Furthermore, several of these compounds also possess a second, decalin ring system, the formation of which is highly reminiscent of the reactions catalyzed by LovB and solanapyrone synthase (see above).…”

Characterization of the biosynthetic gene cluster for maklamicin, a spirotetronate-class antibiotic of the endophytic Micromonospora sp. NBRC 110955

“…With respect to the carbon chain between the cyclohexene and the decalin units, a four-carbon chain linker of maklamicin, in addition to the similar four-carbon chain linkers in nomimicin (Igarashi et al 2012) (Fig. 1) and PA46101 compounds (Matsumoto et al 1989), are the shortest ever such carbon chains reported in the family of spirotetronates.…”

Recent advances in the field of bioactive tetronates

“…PA-46101 in 1990. [80][81][82] These molecules are characterized by an additional decalin unit connected to the 11-membered macrocycle and vary mainly in the decoration of their carbon backbone. The decalin unit mentioned here is also a common structural element of the core structures of the medium-sized spirotetronates described in the following section.…”

“…In contrast to maklamicin, nomimicin displays antifungal activities, suggesting a role of the hydroxylation pattern in determining the antibiotic activity. 81 Medium-sized spirotetronates (CHL/KIJ/TCA-family): central ring system ¼ C 13…”