Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

Caffrey, Patrick; Poire, Eimear De; Sheehan, James P.; Sweeney, Paul

doi:10.1007/s00253-016-7474-z

Cited by 37 publications

(53 citation statements)

References 121 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: 91%

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: 91%

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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“…One intriguing feature of the candicidin PKS is that the KR of module 2 is B1 type and is predicted to give a (2R, 3R)-2-methyl-3-hydroxyacyl-ACP. 1,22 However, NMR analysis of candicidin D indicates that the alcohol at this position (C-41) has the opposite stereochemistry. 8 This anomaly might be explained by further work on the second modules of aromatic polyene PKSs.…”

Section: Predicting the Stereostructure Of 67-121cmentioning

confidence: 99%

“…Since that time, several of these compounds have been used as antibiotics, antiparasitic drugs and preservatives, and other possible applications have been proposed. 1,2 Polyenes interact with ergosterol to disrupt membrane functions in sensitive cells. In fungal pathogens, this vulnerability is not easily overcome by resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

New insights into polyene macrolide biosynthesis in Couchioplanes caeruleus

2017

Self Cite

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Couchioplanes caeruleus DSM43634 synthesises 67-121C, an aromatic heptaene macrolide that contains a mannosyl-mycosaminyl disaccharide. An improved draft genome sequence was used to obtain the biosynthetic gene cluster for this antifungal. Bioinformatic analysis of the polyketide synthase indicated that extension modules 7 and 8 contain A-type ketoreductase and dehydratase domains. These modules are therefore predicted to form cis double bonds. The deduced stereostructure of the 67-121C macrolactone is identical to that experimentally determined for the partricin subgroup of aromatic heptaenes. Some of these polyenes are N-methylated on the aminoacetophenone moiety. The C. caeruleus AceS protein was shown to methylate 4-aminoacetophenone and esters of 4-aminobenzoate, but not 4-aminobenzoate. This suggests that the substrate specificity of AceS prevents it from interfering with folate biosynthesis. The methyltransferase should be valuable for chemoenzymatic alkylation of compounds that contain aminobenzoyl moieties.

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“…A significant number of these secondary metabolites produced by actinomycetes were utilized further as the lead compounds in the field of medicine as clinically important anticancer, antibiotic, anti-inflammatory, antiviral, antiparasitic, and antioxidant drugs (Bérdy, 2005;Subramani and Aalbersberg, 2012;Manivasagan et al, 2014;Abdelmohsen et al, 2015). Among them are polyene macrolide antibiotics, such as nystatin, amphotericin, candicidin, and pimaricin, which are potent antifungal compounds that are comprised typically of a polyketide core macrolactone ring with about 20-40 carbon atoms, including 3-8 conjugated double bonds (Figure 1; Caffrey et al, 2016). The major antifungal mechanism of these polyene antibiotics is believed to be the formation of ion channels via fungal ergosterol binding that mediates the leakage of cellular K + and Mg 2+ , which leads to the death of fungal cells (Bolard, 1986;Neumann et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Stimulated Biosynthesis of an C10-Deoxy Heptaene NPP B2 via Regulatory Genes Overexpression in Pseudonocardia autotrophica

et al. 2020

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Polyene macrolides, such as nystatin A1, amphotericin B, and NPP A1, belong to a large family of valuable antifungal polyketide compounds that are typically produced by soil actinomycetes. Previously, NPP B1, a novel NPP A1 derivative harboring a heptaene core structure, was generated by introducing two amino acid substitutions in the putative NADPH-binding motif of the enoyl reductase domain in module 5 of the NPP A1 polyketide synthase in Pseudonocardia autotrophica. This derivative showed superior antifungal activity to NPP A1. In this study, another novel derivative called NPP B2 was developed, which lacks a hydroxyl group at the C10 position by site-specific gene disruption of the P450 hydroxylase NppL. To stimulate the extremely low expression of the NPP B2 biosynthetic pathway genes, the 32-kb NPP-specific regulatory gene cluster was overexpressed via site-specific chromosomal integration. The extra copy of the six NPP-specific regulatory genes led to a significant increase in the NPP B2 yield from 0.19 to 7.67 mg/L, which is the highest level of NPP B2 production ever achieved by the P. autotrophica strain. Subsequent in vitro antifungal activity and toxicity studies indicated that NPP B2 exhibited similar antifungal activity but significantly lower hemolytic toxicity than NPP B1. These results suggest that an NPP biosynthetic pathway refactoring and overexpression of its pathway-specific regulatory genes is an efficient approach to stimulating the production of an extremely low-level metabolite, such as NPP B2 in a pathway-engineered rare actinomycete strain.

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Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

Cited by 37 publications

References 121 publications

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

New insights into polyene macrolide biosynthesis in Couchioplanes caeruleus

Stimulated Biosynthesis of an C10-Deoxy Heptaene NPP B2 via Regulatory Genes Overexpression in Pseudonocardia autotrophica

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