Microbial Genomics as a Guide to Drug Discovery and Structural Elucidation:  ECO-02301, a Novel Antifungal Agent, as an Example

McAlpine, James B.; Bachmann, Brian O.; Piraee, Mahmood; Tremblay, Steve; Alarco, Anne Marie; Zazopoulos, Emmanuel; Farnet, Chris M.

doi:10.1021/np0401664

Cited by 210 publications

(148 citation statements)

References 8 publications

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“…org/index.php), 58 and many more are continually being discovered through large-scale metagenomics sequencing efforts. 59,60 We used the BRENDA enzyme/ligand database, filtering with "Enzyme, Ligand" and "exact") to confirm the existence of catabolism pathways and organisms that carry such pathways.…”

Section: ■ Methodsmentioning

confidence: 99%

Development of a Transcription Factor-Based Lactam Biosensor

et al. 2017

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Lactams are an important class of commodity chemicals used in the manufacture of nylons, with millions of tons produced every year. Biological production of lactams could be greatly improved by high-throughput sensors for lactam biosynthesis. To identify biosensors of lactams, we applied a chemoinformatic approach inspired by small molecule drug discovery. We define this approach as analogue generation toward catabolizable chemicals or AGTC. We discovered a lactam biosensor based on the ChnR/Pb transcription factor-promoter pair. The microbial biosensor is capable of sensing ε-caprolactam, δ-valerolactam, and butyrolactam in a dose-dependent manner. The biosensor has sufficient specificity to discriminate against lactam biosynthetic intermediates and therefore could potentially be applied for high-throughput metabolic engineering for industrially important high titer lactam biosynthesis.

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Section: ■ Methodsmentioning

confidence: 99%

Development of a Transcription Factor-Based Lactam Biosensor

et al. 2017

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“…As the corresponding genes are organized in clusters and bioinformatic tools allow a reasonable prediction of the pathway product, this bioactivityindependent approach can directly target structural novelty. On a pioneering work of this type, scientists at Ecopia Biosciences (now Thallion Pharmaceuticals, Montreal, QC, Canada) identified ECO-02301, a linear polyene from Streptomyces aizunensis with antifungal activity 28 and ECO-0501, a glycosidic polyketide from Amycolatopsis orientalis with activity against Gram-positive pathogens, including MDR isolates (Figure 1). 29 In a similar approach, a novel cyclic lipopeptide, designated orfamide (Figure 1), was identified from the Pseudomonas fluorescens genome.…”

Section: Approaches Leading To New Antibiotic Classesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

215

122

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New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

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“…Genes responsible for the formation of 2-amino-3-hydroxy-cyclopenta-2-enone, which is found in several natural products, including bafilomycin B 1 , virustomycin A, 8 reductinomycin. 36 asukamycin 37 and ECO-02301, 38 were found upstream of genes encoding type-I PKS. The formation of 2-amino-3-hydroxy-cyclopenta-2-enone from 5-aminolevulinate through 2 steps of an enzymatic reaction has been reported.…”

Section: Characterization Of Bafilomycin Biosynthesismentioning

confidence: 99%

Characterization of bafilomycin biosynthesis in Kitasatospora setae KM-6054 and comparative analysis of gene clusters in Actinomycetales microorganisms

et al. 2017

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(setamycin) produced by Kitasatospora setae KM-6054 belong to the plecomacrolide family, which exhibit antibacterial, antifungal, antineoplastic and immunosuppressive activities. An analysis of gene clusters from K. setae KM-6054 governing the biosynthesis of bafilomycins revealed that it contains five large open reading frames (ORFs) encoding the multifunctional polypeptides of bafilomycin polyketide synthases (PKSs). These clustered PKS genes, which are responsible for bafilomycin biosynthesis, together encode 11 homologous sets of enzyme activities, each catalyzing a specific round of polyketide chain elongation. The region contains an additional 13 ORFs spanning a distance of 73 287 bp, some of which encode polypeptides governing other key steps in bafilomycin biosynthesis. Five ORFs, BfmB, BfmC, BfmD, BfmE and BfmF, were involved in the formation of methoxymalonyl-acyl carrier protein (ACP). Two possible regulatory genes, bfmR and bfmH, were found downstream of the above genes. A gene-knockout analysis revealed that BfmR was only a transcriptional regulator for the transcription of bafilomycin biosynthetic genes. Two genes, bfmI and bfmJ, were found downstream of bfmH. An analysis of these gene-disruption mutants in addition to an enzymatic analysis of BfmI and BfmJ revealed that BfmJ activated fumarate and BfmI functioned as a catalyst to form a fumaryl ester at the C21 hydroxyl residue of bafilomycin A 1 . A comparative analysis of bafilomycin gene clusters in K. setae KM-6054, Streptomyces lohii JCM 14114 and Streptomyces griseus DSM 2608 revealed that each ORF of both gene clusters in two Streptomyces strains were quite similar to each other. However, each ORF of gene cluster in K. setae KM-6054 was of lower similarity to that of corresponding ORF in the two Streptomyces species.

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Microbial Genomics as a Guide to Drug Discovery and Structural Elucidation: ECO-02301, a Novel Antifungal Agent, as an Example

Cited by 210 publications

References 8 publications

Development of a Transcription Factor-Based Lactam Biosensor

Development of a Transcription Factor-Based Lactam Biosensor

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Characterization of bafilomycin biosynthesis in Kitasatospora setae KM-6054 and comparative analysis of gene clusters in Actinomycetales microorganisms

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