Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds

Devine, Rebecca; McDonald, Hannah; Qin, Zhiwei; Arnold, Corinne; Noble, Katie; Chandra, Govind; Wilkinson, Barrie; Hutchings, Matthew I.

doi:10.1016/j.chembiol.2020.12.011

Cited by 22 publications

(30 citation statements)

References 38 publications

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confidence: 99%

“…Phenyltetracenoid polyketides, including fasamycins, − formicamycins, ,, naphthacemycins, − streptovertimycins, and accramycins, , are a class of Streptomyces metabolites possessing a partially reduced 1-phenyltetracene core. They have attracted attention due to their activity against antibiotic-resistant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). − ,− Some also inhibited Poly(ADP-ribose) polymerase-1 (PARP1) and protein tyrosine phosphatase-1B (PTP-1B) . More than 90 members of this class of polyketides have been reported. − They can be categorized into four subclasses according to their structures, i.e., fasamycin-type, formicamycin-type, naphthacemycin-A-type, and naphthacemycin-C-type, as represented by fasamycin A, formicamycin A, naphthacemycin A 1 , and naphthacemycin C 1 , respectively (Figure ).…”

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Antibacterial and Cytotoxic Phenyltetracenoid Polyketides from Streptomyces morookaense

et al. 2021

J. Nat. Prod.

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Formicapyridine-type racemates, streptovertidines A (1) and B (2), a 7,24-seco-fasamycin, streptovertidione (3), and the fasamycin-type streptovertimycins I−T (4−15), together with 13 known fasamycin congeners (16−28), were isolated from soilderived Streptomyces morookaense SC1169. Their structures were elucidated by extensive spectroscopic analysis and theoretical computations of ECD spectra. The fasamycin-type compounds 5, 8−12, 14, and 15 exhibited activity against the drug-resistant bacteria MRSA and VRE (MIC: 1.25−10.0 μg/mL). All isolates, except 3, 4, 10, and 24, displayed cytotoxicity against at least one of the human carcinoma A549, HeLa, HepG2, and MCF-7 cells (IC 50 < 10.0 μM), of which some were also cytotoxic to the noncancerous Vero cells. Taken together, the activity data demonstrated that the fasamycin-type compounds were more selective to the tested bacteria over the mammalian cells. Structure−activity relationship analysis suggested that chlorination at C-2 in antibacterial fasamycin-type compounds improves the activity and selectivity to the bacteria. Theoretical simulations of reaction paths and chemical reactions for conversion of 3 to 1 were carried out and supported that the pyridine ring formation in formicapyridines proceeds nonenzymatically via 1,5-dicarbonyl condensation with ammonia.

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Antibacterial and Cytotoxic Phenyltetracenoid Polyketides from Streptomyces morookaense

et al. 2021

J. Nat. Prod.

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“…Whereas investigation of laboratory growth conditions would be a precious help in identifying DIRLs function it is to note that only few bacteria among those listed in this study have been grown in a laboratory. Still, the CRISPR/Cas9 mutagenesis method has been developed recently for S. formicae KY that is grown in laboratory conditions (37). This is particularly interesting since it is known that environmental growth conditions in uence the secondary metabolism molecules expression.…”

Section: Discussionmentioning

confidence: 99%

Investigation of dirigent like domains from bacterial genomes

Bardin

Rousselot‐Pailley

Tron

et al. 2022

Preprint

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BACKGROUND: Dirigent proteins (DIRs) have been named after plant proteins capable to direct the stereoselectivity in the coupling of radicals from various metabolites. Recently, evidence that DIR proteins occurred far more abundantly than previously thought (i.e., beyond plant kingdom) have been obtained.RESULTS: Analyzes of structural and functional genomic data led to the identification of the Pfam PF03018 domain as characteristic of DIR proteins. This domain has been further identified in the sequence of bacterial proteins therefore named as DIR-like (DIRL). The objective of this study was to perform a thorough bioinformatic analysis on these DIRLs to highlight any information leading to the selection of candidate bacteria for further cloning, purification, and characterization of bacterial DIRs. CONCLUSIONS: From studies of primary structures, predictions of their secondary and tertiary structures, prediction of DIRL signals sequences, analysis of their gene organization and potential regulation, a list of primary bacterial candidates is proposed.

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“…Since the identification of the first of those antifungals, the depsipeptide dentigerumycin [ 87 ] ( Figure 4 ), many other novel compounds have been isolated from bacteria associated with fungus-growing ants, like the halogenated NRPS-PKS hybrids colibrimycins [ 88 ] and collismycins [ 89 ] ( Figure 4 ), novel quinones [ 90 ], diverse macrolides showing both antifungal and antileishmanial activities [ 91 ] or the non-ribosomal peptide attinimicin, an iron-dependent antifungal [ 92 ]. Formicamycins ( Figure 4 ), pentacyclic type II PKS products from Streptomyces formicae (a strain isolated from the tree-associated Tetraponera ants which shows an impressive secondary metabolism potential [ 93 ]), show potent activity against Gram-positive pathogens without apparent generation of spontaneous resistance [ 94 , 95 , 96 , 97 ]. Formicamycins have also been recently isolated from a soil Streptomyces strain [ 98 ].…”

Section: Insect-associated Bacteriamentioning

confidence: 99%

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

Santos‐Aberturas

Vior

2022

Antibiotics

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Bacterial secondary metabolites represent an invaluable source of bioactive molecules for the pharmaceutical and agrochemical industries. Although screening campaigns for the discovery of new compounds have traditionally been strongly biased towards the study of soil-dwelling Actinobacteria, the current antibiotic resistance and discovery crisis has brought a considerable amount of attention to the study of previously neglected bacterial sources of secondary metabolites. The development and application of new screening, sequencing, genetic manipulation, cultivation and bioinformatic techniques have revealed several other groups of bacteria as producers of striking chemical novelty. Biosynthetic machineries evolved from independent taxonomic origins and under completely different ecological requirements and selective pressures are responsible for these structural innovations. In this review, we summarize the most important discoveries related to secondary metabolites from alternative bacterial sources, trying to provide the reader with a broad perspective on how technical novelties have facilitated the access to the bacterial metabolic dark matter.

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Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds

Cited by 22 publications

References 38 publications

Antibacterial and Cytotoxic Phenyltetracenoid Polyketides from Streptomyces morookaense

Antibacterial and Cytotoxic Phenyltetracenoid Polyketides from Streptomyces morookaense

Investigation of dirigent like domains from bacterial genomes

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

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