Jogyamycin, a new antiprotozoal aminocyclopentitol antibiotic, produced by Streptomyces sp. a-WM-JG-16.2

Abstract

During our search for new antiprotozoal (antimalarial and antitrypanosomal) agents, we have tested culture extracts of soil microorganisms from a variety of sources, including those isolated by the Kitasato Institute for Life Sciences and the Bioresource Laboratories, MicroBiopharm Japan Corporation. We have previously discovered a variety of microbial metabolites exhibiting antiprotozoal, 1,2 antimalarial 3,4 and antitrypanosomal properties. 5,6 Recently, we have isolated a new derivative of pactamycin, designated as jogyamycin (Figure 1), from a culture broth of Streptomyces sp. a-WM-JG-16.2. This compound has proved to have potent antiprotozoal activity (Table 2). Here, we report the fermentation, isolation, structure elucidation and biological activity of this novel aminocyclopentitol antibiotic.The producing organism, strain a-WM-JG-16.2 was isolated from a soil sample collected in Jogjakarta, Indonesia, using the sucrose density gradient centrifugation method. 7 Using the basic local alignment search tool (BLAST), we compared the 16S rRNA gene sequences available in the EzTaxon server to identify the species of strain a-WM-JG-16.2. Streptomyces sp. a-WM-JG-16.2 was classified as a species of the genus Streptomyces; the 16S rRNA gene sequence comparison showing a 100% similarity with S. griseoruber NBRC12873 (AB184209).The strain was cultured on a rotary shaker (220 r.p.m.) at 28 1C for 5 days in 500-ml Erlenmeyer flasks (20 flasks) containing 50 ml of a production medium containing 2% rice starch (Rose brand, Cikampek, Indonesia), 2% glucose (Univar, Sydney, NSW, Australia), 2% soybean meal (J-Oil Mills, Tokyo, Japan), 0.5% yeast extract

Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity

“…Additionally, the human embryonic cell line for which pactamycin’s toxicity has been established (MRC-5) was assayed for comparison. 5,4b The results for all derivatives are summarized in Table 4. As anticipated, pactamycin (entry 1) displayed exceptional potency, showing nanomolar inhibition against all three carcinoma cell lines.…”

“…Researchers at Upjohn showed it to be active against Gram-positive and Gram-negative bacteria as well as against a number of cancer cell lines in vitro. 4 More recent biological studies have demonstrated pactamycin to have potent antiviral (complete inhibition of polio-infected HeLa cells at 10 −7 M) and antiprotozoal qualities (P.f. K1: IC 50 = 14.2 nM).…”

“…5,4b Unfortunately, this promising biological profile is hindered by pactamycin’s high cytotoxicity against human eukaryotic cell lines (MRC-5: IC 50 = 95 nM). 5,4b X-ray crystallographic studies have shown that the source of this activity stems from pactamycin’s ability to bind to the 30S ribosomal subunit acting as an RNA dinucleotide mimic. 6 A complex array of H-bonding interactions within the 30S site enables pactamycin to act as a universal inhibitor of translocation.…”

Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

“…Within the ribosomal subunit in which it interacts, pactamycin mimics an RNA dinucleotide through interactions of its aniline and salicylate moieties with stem loops in the 16S RNA (10). Unfortunately, therapeutic benefits have yet to be realized due to high cytotoxicity (IC 50 95 nM against human diploid embryonic cell line MRC-5) (11). Pactamycin is a prototypical example of a promising bioactive natural product whose complexity hampers investigation of structure/activity relationships (SAR) that might lead to a serviceable therapeutic application and/or better understanding of intrinsic bioactivity.…”

Diastereoselective Synthesis of the Aminocyclitol Core of Jogyamycin via an Allene Aziridination Strategy

“…1 Jogyamycin itself exhibits potent antiprotozoal activity against important diseases including malaria and African sleeping sickness, while pactamycin and analogs have been shown to possess anticancer, antiviral, and antimicrobial activity in addition to antiprotozoal activity. 1,2 Crystal structures of pactamycin with the ribosomal 30S subunit indicate it acts as a universal inhibitor of translocation in a highly conserved region of the ribosome, explaining the wide range of biological activity exhibited by this family of molecules. 3 Subtle structural changes in the aminocyclitol motif have been shown to alter the activity of these natural products significantly.…”