Streptomyces venezuelae ISP5230 Maintains Excretion of Jadomycin upon Disruption of the MFS Transporter JadL Located within the Natural Product Biosynthetic Gene Cluster

Forget, Stephanie M.; McVey, Jennifer; Vining, L. C.; Jakeman, David L.

doi:10.3389/fmicb.2017.00432

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…Chloramphenicol is a broad-spectrum antibacterial, active against both Gram-positive and Gram-negative bacteria and inhibits protein synthesis by binding to the 50S ribosome subunit [40,62]. The jadomycins are angucycline antibiotics with a cytotoxic activity whose expression is induced via ethanol, phage or yeast co-culture shock when grown in minimal media [63]. Regulation of jadomycin biosynthesis by CSRs is complex, but the current model begins with the gamma-butyrolactone SVB1 modulating the activity of the γ-butyrolactone receptor JadR3, which activates transcription of the gene encoding the OmpR-type atypical response regulator jadR1 and represses jadR2 .…”

Section: Coordinate Regulation Of Bgcsmentioning

confidence: 99%

Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis

et al. 2019

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Discovering new antibiotics is vital to combat the growing threat of antimicrobial resistance. Most currently used antibiotics originate from the natural products of actinomycete bacteria, particularly Streptomyces species, that were discovered over 60 years ago. However, genome sequencing has revealed that most antibiotic-producing microorganisms encode many more natural products than previously thought. Biosynthesis of these natural products is tightly regulated by global and cluster situated regulators (CSRs), most of which respond to unknown environmental stimuli, and this likely explains why many biosynthetic gene clusters (BGCs) are not expressed under laboratory conditions. One approach towards novel natural product discovery is to awaken these cryptic BGCs by re-wiring the regulatory control mechanism(s). Most CSRs bind intergenic regions of DNA in their own BGC to control compound biosynthesis, but some CSRs can control the biosynthesis of multiple natural products by binding to several different BGCs. These cross-cluster regulators present an opportunity for natural product discovery, as the expression of multiple BGCs can be affected through the manipulation of a single regulator. This review describes examples of these different mechanisms, including specific examples of cross-cluster regulation, and assesses the impact that this knowledge may have on the discovery of novel natural products.

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Section: Coordinate Regulation Of Bgcsmentioning

confidence: 99%

Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis

et al. 2019

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“…Studies of compensation have focused on single resistances (e.g., [ 17 , 20 , 23 , 26 ]). However, resistance mutations often interact such that the fitness cost of multiple resistance tends to differ from that expected given the effects of each resistance [ 24 , 27 ]. These epistatic interactions might originate from the fact that resistance mutations affect interconnected functions in the cell [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Multidrug-resistant bacteria compensate for the epistasis between resistances

et al. 2017

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Mutations conferring resistance to antibiotics are typically costly in the absence of the drug, but bacteria can reduce this cost by acquiring compensatory mutations. Thus, the rate of acquisition of compensatory mutations and their effects are key for the maintenance and dissemination of antibiotic resistances. While compensation for single resistances has been extensively studied, compensatory evolution of multiresistant bacteria remains unexplored. Importantly, since resistance mutations often interact epistatically, compensation of multiresistant bacteria may significantly differ from that of single-resistant strains. We used experimental evolution, next-generation sequencing, in silico simulations, and genome editing to compare the compensatory process of a streptomycin and rifampicin double-resistant Escherichia coli with those of single-resistant clones. We demonstrate that low-fitness double-resistant bacteria compensate faster than single-resistant strains due to the acquisition of compensatory mutations with larger effects. Strikingly, we identified mutations that only compensate for double resistance, being neutral or deleterious in sensitive or single-resistant backgrounds. Moreover, we show that their beneficial effects strongly decrease or disappear in conditions where the epistatic interaction between resistance alleles is absent, demonstrating that these mutations compensate for the epistasis. In summary, our data indicate that epistatic interactions between antibiotic resistances, leading to large fitness costs, possibly open alternative paths for rapid compensatory evolution, thereby potentially stabilizing costly multiple resistances in bacterial populations.

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“…Indeed, the reported yield for sugar modified 58a suggests production of 3 µgmL -1 in comparison to 22 µgmL -1 for its L-digitoxylated counterpart, Jd DS (36). 44,47 Likewise, for D-olivosylated jadomycin (58a) the reported yield suggested 0.3 µgmL -1 , in contrast to standard Jd B (2) reported to reach up to 69 µgmL -1 . 5,44,45 In all cases, these complemented systems were reliant on the relaxed specificity of native JadS to catalyze glycosyltransfer and deliver the sugar-modified jadomycin analogues.…”

Section: Sugar Modification Of Jadomycinsmentioning

confidence: 87%

The expansive library of jadomycins

2018

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The jadomycin family of natural products was discovered from Streptomyces venezuelae ISP5230 in the 1990s. Subsequent identification of the biosynthetic gene cluster along with synthetic efforts established that incorporation of an amino acid into the polyaromatic angucycline core occurs non-enzymatically. Over two decades, the precursor-directed biosynthetic potential of the jadomycins has been heavily exploited, generating a library exceeding 70 compounds. This review compiles the jadomycins that have been isolated and characterized to date; these include jadomycins incorporating proteinogenic and non-proteinogenic amino acids, semi-synthetic derivatives, biosynthetic shunt products, compounds isolated in structural gene deletion studies, and deoxysugar sugar variant jadomycins produced by deletion or heterologous expression of sugar biosynthetic genes.

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Streptomyces venezuelae ISP5230 Maintains Excretion of Jadomycin upon Disruption of the MFS Transporter JadL Located within the Natural Product Biosynthetic Gene Cluster

Cited by 9 publications

References 34 publications

Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis

Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis

Multidrug-resistant bacteria compensate for the epistasis between resistances

The expansive library of jadomycins

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