A new antibiotic, medermycin.

Takano, Shoichi; Hasuda, Katsumi; Itō, Akira; Koide, Yuji; Ishii, Fumio; Haneda, Isoko; Chihara, Shiro; Koyama, Yasuo

doi:10.7164/antibiotics.29.765

Cited by 75 publications

(52 citation statements)

References 2 publications

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“…The previously reported MIC values for PNQs against S. aureus strains range from 0.9 to 3.6 M for granaticin B (13), from 7 to 53 M for kalafungin (15), and from 0.4 to 1.7 M for medermycin (14). In accordance with this data, antistaphylococcal activity of the PNQs was also observed here as activity against planktonic cells and as effective inhibition of biofilm formation.…”

Section: Inhibition Of Biofilm Formation By the Alnumycinssupporting

confidence: 77%

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Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species

Oja

San-Martin-Galindo

Taguchi

et al. 2015

Antimicrob Agents Chemother

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dStreptomyces bacteria are renowned for their ability to produce bioactive secondary metabolites. Recently, synthetic biology has enabled the production of intermediates and shunt products, which may have altered biological activities compared to the end products of the pathways. Here, we have evaluated the potential of recently isolated alnumycins and other closely related pyranonaphthoquinone (PNQ) polyketides against Staphylococcus aureus biofilms. The antimicrobial potency of the compounds against planktonic cells and biofilms was determined by redox dye-based viability staining, and the antibiofilm efficacy of the compounds was confirmed by viable counting. A novel antistaphylococcal polyketide, alnumycin D, was identified. Unexpectedly, the C-ribosylated pathway shunt product alnumycin D was more active against planktonic and biofilm cells than the pathway end product alnumycin A, where a ribose unit has been converted into a dioxane moiety. The evaluation of the antibiofilm potential of other alnumycins revealed that the presence of the ribose moiety in pyranose form is essential for high activity against preformed biofilms. Furthermore, the antibiofilm potential of other closely related PNQ polyketides was examined. Based on their previously reported activity against planktonic S. aureus cells, granaticin B, kalafungin, and medermycin were also selected for testing, and among them, granaticin B was found to be the most potent against preformed biofilms. The most active antibiofilm PNQs, alnumycin D and granaticin B, share several structural features that may be important for their antibiofilm activity. They are uncharged, glycosylated, and also contain a similar oxygenation pattern of the lateral naphthoquinone ring. These findings highlight the potential of antibiotic biosynthetic pathways as a source of effective antibiofilm compounds.

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Section: Inhibition Of Biofilm Formation By the Alnumycinssupporting

confidence: 77%

“…ermycin (lactoquinomycin; Fig. 1) were found to be active against multiresistant S. aureus strains (13,14). Research in the 1960s also showed that the nonglycosylated wide-spectrum antibiotic kalafungin ( Fig.…”

mentioning

confidence: 99%

Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species

Oja

San-Martin-Galindo

Taguchi

et al. 2015

Antimicrob Agents Chemother

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“…K73 (Takano et al, 1976). Its structure was shown (Tatsuta et al, 1990) to be identical with lactoquinomycin A, independently characterized as an anticancer compound from Streptomyces tanashiensis Okabe et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Cloning, sequencing and heterologous expression of the medermycin biosynthetic gene cluster of Streptomyces sp. AM-7161: towards comparative analysis of the benzoisochromanequinone gene clusters

et al. 2003

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Medermycin is a Streptomyces aromatic C-glycoside antibiotic classified in the benzoisochromanequinones (BIQs), which presents several interesting biosynthetic problems concerning polyketide synthase (PKS), post-PKS tailoring and deoxysugar pathways. The biosynthetic gene cluster for medermycin (the med cluster) was cloned from Streptomyces sp. AM-7161. Completeness of the clone was proved by the heterologous expression of a cosmid carrying the entire med cluster in Streptomyces coelicolor CH999 to produce medermycin. The DNA sequence of the cosmid (36 202 bp) revealed 34 complete ORFs, with an incomplete ORF at either end. Functional assignment of the deduced products was made for PKS and biosynthetically related enzymes, tailoring steps including strereochemical control, oxidation, angolosamine pathway, C-glycosylation, and regulation. The med cluster was estimated to be about 30 kb long, covering 29 ORFs. An unusual characteristic of the cluster is the disconnected organization of the minimal PKS genes: med-ORF23 encoding the acyl carrier protein is 20 kb apart from med-ORF1 and med-ORF2 for the two ketosynthase components. Secondly, the six genes (med-ORF14, 15, 16, 17, 18 and 20) for the biosynthesis of the deoxysugar, angolosamine, are all contiguous. Finally, the finding of a glycosyltransferase gene, med-ORF8, suggests a possible involvement of conventional C-glycosylation in medermycin biosynthesis. Comparison among the three complete BIQ gene clusters – med and those for actinorhodin (act) and granaticin (gra) – revealed some common genes whose deduced functions are unavailable from database searches (the ‘unknowns’). An example is med-ORF5, a homologue of actVI-ORF3 and gra-ORF18, which was highlighted by a recent proteomic analysis of S. coelicolor A3(2).

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“…The feasibility of this approach was first demonstrated in work by David Hopwood and colleagues (Hopwood et al, 1985). Following the cloning of the biosynthetic genes for the antibiotic actinorhodin from Streptomyces coelicolor (Malpartida & Hopwood, 1984), Hopwood and coworkers cloned some or all of these genes into the producers of the antibiotics medermycin (Takano et al, 1976) and dihydrogranaticin (Corbaz et al, 1957), respectively. The transformant of the medermycin producer, Streptomyces sp.…”

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confidence: 99%

Combinatorial biosynthesis—Potential and problems

Floss

2006

Journal of Biotechnology

140

114

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Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author's laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations. KeywordsCombinatorial biosynthesis; metabolic engineering; natural products; rifamycin; maytansinoids; polyketides Combinatorial biosynthesis can be defined as the application of genetic engineering to modify biosynthetic pathways to natural products in order to produce new and altered structures using nature's biosynthetic machinery. The feasibility of this approach was first demonstrated in work by David Hopwood and colleagues (Hopwood et al., 1985). Following the cloning of the biosynthetic genes for the antibiotic actinorhodin from Streptomyces coelicolor (Malpartida & Hopwood, 1984), Hopwood and coworkers cloned some or all of these genes into the producers of the antibiotics medermycin (Takano et al., 1976) and dihydrogranaticin (Corbaz et al., 1957), respectively. The transformant of the medermycin producer, Streptomyces sp. AM-7161 produced, in addition to medermycin, large amounts of a new compound, mederrhodin A, which carried an additional hydroxy group characteristic of actinorhodin ( Figure 1). The transformant of the dihydrogranaticin producer, Streptomyces violaceoruber Tü 22 produced a new compound, dihydrogranatirhodin, which has the actinorhodin configuration at one and the dihydrogranaticin configuration at the other stereocenter of the isochromane quinone system. This work represents the first, albeit modest, implementation of the concept of combinatorial biosynthesis of natural products. Since then, a large number of examples encompassing a wide range of natural product classes have appeared in the literature, and this approach has been accepted as a useful tool to increase the chemical diversity of natural products (Staunton and Wilkinson, 2001;Walsh, 2002;Rix et al., 2002;Reeves, 2003). Following the author's primary interests, this article focuses on the application of the combinatorial biosynthesis approach to microbial natural products and within these to Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript ...

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A new antibiotic, medermycin.

Cited by 75 publications

References 2 publications

Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species

Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species

Cloning, sequencing and heterologous expression of the medermycin biosynthetic gene cluster of Streptomyces sp. AM-7161: towards comparative analysis of the benzoisochromanequinone gene clusters

Combinatorial biosynthesis—Potential and problems

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