Organizational and Mutational Analysis of a Complete FR-008/Candicidin Gene Cluster Encoding a Structurally Related Polyene Complex

Chen, Shi; Huang, Xi; Zhou, Xing; Bai, Linquan; He, Jialin; Jeong, Ki Jun; Lee, Sang Yup; Deng, Zixin

doi:10.1016/j.chembiol.2003.10.007

Cited by 116 publications

(129 citation statements)

References 42 publications

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“…The bioinformatically identified selvamicin cluster resembles known type I PKS-derived polyene BGCs (30)(31)(32)(33)(34)(35), and a side-by-side comparison with the well-characterized nystatin BGC (36,37) readily reveals the origins of selvamicin's unusual structural features (Fig. 5).…”

Section: Chemistrymentioning

confidence: 99%

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Arnam

Ruzzini

Sit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal compounds from these bacteria, we discovered selvamicin, an unusual antifungal polyene macrolide, in bacterial isolates from two neighboring ant nests. Selvamicin resembles the clinically important antifungals nystatin A1 and amphotericin B, but it has several distinctive structural features: a noncationic 6-deoxymannose sugar at the canonical glycosylation site and a second sugar, an unusual 4-O-methyldigitoxose, at the opposite end of selvamicin’s shortened polyene macrolide. It also lacks some of the pharmacokinetic liabilities of the clinical agents and appears to have a different target. Whole genome sequencing revealed the putative type I polyketide gene cluster responsible for selvamicin’s biosynthesis including a subcluster of genes consistent with selvamicin’s 4-O-methyldigitoxose sugar. Although the selvamicin biosynthetic cluster is virtually identical in both bacterial producers, in one it is on the chromosome, in the other it is on a plasmid. These alternative genomic contexts illustrate the biosynthetic gene cluster mobility that underlies the diversity and distribution of chemical defenses by the specialized bacteria in this multilateral symbiosis.

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Section: Chemistrymentioning

confidence: 99%

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Arnam

Ruzzini

Sit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…36 An indication for the production of candicidin in S. wadayamensis was already anticipated in previous studies 20 by the use of metabolic probes to promote dereplication. The KS-AT domains from FscB and FscD (gene numbers 17 and 20, respectively, Figure 7) were identified using this methodology.…”

Section: Resultsmentioning

confidence: 97%

“…The mining also indicated a possible metabolite described by the clusters 4 and 16 belonging to the FR-008 BGC, a complex polyene with high similarity to the candicidin gene cluster found in Streptomyces griseus IMRU3570 ( Figure 5). 36 Chen et al 36 originally described this metabolite and its gene cluster in 2003 and throughout this study it was possible to conclude that candicidin and FR-008 are identical compounds.…”

Section: Resultsmentioning

confidence: 99%

Genome Mining of EndophyticStreptomyces wadayamensisReveals High Antibiotic Production Capability

Angolini¹,

Gonçalves²,

Sigrist³

et al. 2016

Journal of the Brazilian Chemical Society

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The actinobacteria Streptomyces wadayamensis A23, an endophitic strain, was recently sequenced and previous work showed qualitatively that the strain inhibits the growth of some pathogens. Herein we report the genome analysis of S. wadayamensis which reveals several antibiotic biosynthetic pathways. Using mass spectrometry, we were able to identify desferoxamines, several antimycins and candicidin, as predicted. Additionally, it was possible to confirm that the biosynthetic machinery of the strain when compared to identified known metabolites is far underestimated. As suggested by biochemical qualitative tests, genome encoded information reveals that the strain A23 has high capability to produce antibiotics.

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“…pJTU50 was transferred into Streptomyces sp. FR-008 by conjugation from Escherichia coli ET12567 carrying RP4 derivative pUZ8002 [8]. Thiostrepton-sensitive and apramycin resistance (Thio S -Apr R ) colonies were counter-selected from the initial Thio R exconjugants after two rounds of nonselective growth to obtain CS103 (Chen and Mao et al, unpublished).…”

Section: Microorganismmentioning

confidence: 99%

“…FR-008 is found to possess the identity to the candicidin complex ( Fig. 1) [8] and holds a greater potential for pharmaceutical utility for its remarkably higher production yield than the originally discovered candicidin producer (Streptomyces griseus IMRU3570).…”

Section: Introductionmentioning

confidence: 99%

The pH Shift and Precursor Feeding Strategy in a Low-Toxicity FR-008/Candicidin Derivative CS103 Fermentation Bioprocess by a Mutant of Streptomyces sp. FR-008

Mao

Wang

Zhang

et al. 2009

Appl Biochem Biotechnol

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CS103, the novel derivative of polyene macrolides antibiotic FR-008/candicidin with lower toxicity has been isolated from the culture mycelia of the mutant of Streptomyces sp. FR-008, with targeted deletions of the fscP cytochrome P450 gene from its chromosome. To enhance biosynthesis of CS103, pH shift and precursor feeding strategy for fermentation process by the mutant of Streptomyces sp. FR-008 in a stirred tank bioreactor was developed. According to the process parameters analysis, the effectiveness of the strategy was examined and confirmed by experiments. A maximal CS103 concentration of 139.98 μg/mL was obtained, 2.05-fold higher than that in the pHuncontrolled fermentation. Compared to other three cases as pH-uncontrolled, pHcontrolled, and two-stage pH-controlled batch cultures, the proposed "pH shift and precursor feeding strategy" effectively avoided the scarcity of the antibiotic precursor, increased the CS103 yield from biomass (Y P/X ) and substrate (Y P/S ) by 110.61% and 48.52%, respectively, and at the time the fermentation time was shortened from 120 to 96 h. The highest CS103 production rate (1.46 μg mL −1 h −1 ) of the pH shift and precursor feeding strategy was 284.21%, 97.30%, and 58.70% higher than that of pH-uncontrolled, pH-controlled, and two-stage pH-controlled batch culture cases, respectively.

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Organizational and Mutational Analysis of a Complete FR-008/Candicidin Gene Cluster Encoding a Structurally Related Polyene Complex

Cited by 116 publications

References 42 publications

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Genome Mining of EndophyticStreptomyces wadayamensisReveals High Antibiotic Production Capability

The pH Shift and Precursor Feeding Strategy in a Low-Toxicity FR-008/Candicidin Derivative CS103 Fermentation Bioprocess by a Mutant of Streptomyces sp. FR-008

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