Pyrroxamycin, a new antibiotic. Taxonomy, fermentation, isolation, structure determination and biological properties.

Abstract

A strain of streptomycete was found to produce a new antibiotic pyrroxamycin. This compoundwas isolated from the culture broth of Streptomyces sp. S46506. The chemical structure was determined to be 4>5-dichloro-2-(6/,8/-dichloro-4/Jfir-r,3/-benzodioxin-4/-yl)-3nitropyrrole by its chemical character and XHand 13C NMRspectral analysis. Pyrroxamycin was active against Gram-positivebacteria and dermatophytes. In the course of our screening program for new antibiotics, a streptomycete, strain S46506, designated as Streptomyces sp. S46506 was found to produce a new antibiotic named pyrroxamycin (1). This compound was previously called SS46506A substance1}. The chemical structure of pyrroxamycin, a new antibiotic related to pyrrolomycins, was determined to be 4,5-dichloro-2-(6',8/-dichloro-4'iif-r, S'-benzodioxm-^-yO-S-nitropyrrole by its chemical character and XHand 13C NMRspectral analysis. Pyrroxamycin was active against Gram-positive bacteria and dermatophytes. This paper deals with taxonomy of producing strain, fermentation, isolation, physico-chemical properties, chemical structure and biological properties of pyrroxamycin. Taxonomy Strain S46506 was isolated from a soil sample collected at Kamagaya City, Chiba Prefecture, Japan. The mediumused for actinomycete isolation was tomato juice-oatmeal agar composed of oatmeal 20 g, tomato juice (centrifuged supernatant, 10,000 rpm, 10 minutes) 100 ml, distilled water 900 ml, Bacto agar (Difco) 20 g, nystatin 40 mg, cycloheximide 40 mg and novobiocin 10 mg. The strain has been deposited at The Fermentation Research Institute, Agency of Industrial Science and Technology, Japan, where it has been assigned accession number FERMP-8020. Taxonomic studies were carried out according to the methods described by Shirling and Gottlieb2) and of Waksman3). The color notations were from the ISCC-NBSCentroid Color Charts1. The inoculation of strain S46506 onto various media was carried out using the washed cells cultured in yeaststarch broth at 28°C for 5 days on a reciprocal shaker. Morphological observations were made of the cultures grown at 28°C for 7~21 days on thin potato-carrot agar and water agar4). Mature spore chains had 10 or more spores in the form of spirals (Fig. 1). Spirals were observed in spots on the above media. The spores were oval or cylindrical and 0.5~0.8 x0.8~1.2^min size with a smooth surface under an electron microscope (Fig. 2). No sporangia or flagellated spores were observed.

Biosynthesis of pyrrolnitrin and other phenylpyrrole derivatives by bacteria (up to mid-1999)

“…2 In the following years 1 was isolated from a number of different Pseudomonas species, 5,6 Burkholderia formerly Pseudomonas cepacia, 7,8 Myxococcus fulvus, Corallococcus exiguus, Cystobacter ferrugineus 9 and Enterobacter agglomerans. 10 In addition to 1 a number of structurally different halogenated phenylpyrrole derivatives have been isolated, like pyrrolomycins B-F 2-9 produced by Actinosporangium vitaminophilum, [11][12][13] dioxapyrrolomycin 10 [14][15][16] and neopyrrolomycin 11 17 produced by Streptomyces sp. strains, pyoluteorin 12 produced by Pseudomonas aeruginosa 18 and P. fluorescens, 19 pentabromopseudilin 13 produced by P. bromoutilis 20 and Alteromonas luteoviolaceus 21 and pentachloropseudilin 14 produced by an Actinoplanes sp.…”

Synthesis, Insecticidal, and Acaricidal Activities of Novel 2-Aryl-pyrrole Derivatives Containing Ester Groups

“…In 1987, the American Cyanamid Company isolated and identified dioxapyrrolomycin ( A , Figure ) from a Streptomyces strain and found that dioxapyrrolomycin exhibited moderate broad spectrum insecticidal and miticidal activities . At about the same time, this pyrrole A was also reported by Meiji Seika Kaisha and SS Pharmaceutical Company in Japan as an antibiotic , . However, an oral LD 50 of 14 mg kg 1− to mice showed it to be highly toxic.…”

Nitropyrrole natural products: isolation, biosynthesis and total synthesis

“…The absolute stereochemistry of dioxapyrrolomycin ( 4) at C-6 was determined to be S from the X-ray crystal structure of the corresponding N-methyl derivative. 7,8 In 2005, the structures of pyrrolomycins G ( 5) and H (6) produced in cultures of Streptomyces fumanus were reported by Carter and co-workers. 9 These two pyrrolomycins ( 5) and ( 6) possess both a nitropyrrole moiety and a chiral center with the same absolute stereochemistry at C-6 as dioxapyrrolomycin (4) and were considered to be biosynthetic precursors to dioxapyrrolomycin (4).…”

“…S46506 by Yano and coworkers in 1987. 7 Dioxapyrrolomycin (4) was also the first member of nitropyrrole-containing natural products to contain a stereogenic centre. The absolute stereochemistry of dioxapyrrolomycin ( 4) at C-6 was determined to be S from the X-ray crystal structure of the corresponding N-methyl derivative.…”