A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes

Fabbretti, Attilio; He, Cheng-Guang; Gaspari, Eleonora; Maffioli, Sonia; Brandi, Letizia; Spurio, Roberto; Sosio, Margherita; Jabès, Daniela; Donadio, Stefano

doi:10.1128/aac.05155-14

Cited by 26 publications

(15 citation statements)

References 32 publications

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“…Semi-synthetic derivatization has been successful in fine-tuning thiopeptide spectrum of activity. For example, a derivative of GE2270A has been reported to be highly selective towards Propionibacterium acnes [*42]. Despite their potent activity, thiopeptides suffer from poor aqueous solubility which has hampered their clinical development.…”

Section: Thiopeptidesmentioning

confidence: 99%

RiPP antibiotics: biosynthesis and engineering potential

Hudson

Mitchell

2018

Current Opinion in Microbiology

160

112

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The threat of antibiotic resistant bacterial infections continues to underscore the need for new treatment options. Historically, small molecule metabolites from microbes have provided a rich source of antibiotic compounds, and as a result, significant effort has been invested in engineering the responsible biosynthetic pathways to generate novel analogs with attractive pharmacological properties. Unfortunately, biosynthetic stringency has limited the capacity of non-ribosomal peptide synthetases and polyketide synthases from producing substantially different analogs in large numbers. Another class of natural products, the ribosomally synthesized and post-translationally modified peptides (RiPPs), have rapidly expanded in recent years with many natively displaying potent antibiotic activity. RiPP biosynthetic pathways are modular and intrinsically tolerant to alternative substrates. Several prominent RiPPs with antibiotic activity will be covered in this review with a focus on their biosynthetic plasticity. While only a few RiPP enzymes have been thoroughly investigated mechanistically, this knowledge has already been harnessed to generate new-to-nature compounds. Through the use of synthetic biology approaches, on-going efforts in RiPP engineering hold great promise in unlocking the potential of this natural product class.

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Section: Thiopeptidesmentioning

confidence: 99%

RiPP antibiotics: biosynthesis and engineering potential

Hudson

Mitchell

2018

Current Opinion in Microbiology

160

112

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“…Indeed, screening systems to identify compounds that preferentially inhibit the initiation phase have proved successful [51,52,53]. In addition, our IF3 DL -30S reporter assay can provide novel aspects of the inhibiting mechanism of known 30S-binding drugs.…”

Section: Discussionmentioning

confidence: 99%

Conformational Response of 30S-bound IF3 to A-Site Binders Streptomycin and Kanamycin

et al. 2016

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Aminoglycoside antibiotics are widely used to treat infectious diseases. Among them, streptomycin and kanamycin (and derivatives) are of importance to battle multidrug-resistant (MDR) Mycobacterium tuberculosis. Both drugs bind the small ribosomal subunit (30S) and inhibit protein synthesis. Genetic, structural, and biochemical studies indicate that local and long-range conformational rearrangements of the 30S subunit account for this inhibition. Here, we use intramolecular FRET between the C- and N-terminus domains of the flexible IF3 to monitor real-time perturbations of their binding sites on the 30S platform. Steady and pre-steady state binding experiments show that both aminoglycosides bring IF3 domains apart, promoting an elongated state of the factor. Binding of Initiation Factor IF1 triggers closure of IF3 bound to the 30S complex, while both aminoglycosides revert the IF1-dependent conformation. Our results uncover dynamic perturbations across the 30S subunit, from the A-site to the platform, and suggest that both aminoglycosides could interfere with prokaryotic translation initiation by modulating the interaction between IF3 domains with the 30S platform.

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“…Both are semi-synthetic natural product analogs with high structural similarity to GE37468: LFF571 for treatment of C. difficile and NAI003 for topical treatment of acne (Figure 2). 23,24 Further examination of host-associated microbes from various symbiotic contexts may reveal therapeutically useful molecules and clarify principles of antibiotic deployment in nature. Linking therapeutically useful activity to ecological function may unlock lessons for antibiotic discovery and stewardship.…”

Section: Resultsmentioning

confidence: 99%

Thiopeptide Defense by an Ant’s Bacterial Symbiont

Chang¹,

Rao²,

Longo³

et al. 2019

Preprint

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Fungus-growing ants and their bacterial symbionts have emerged as a model animal-microbe symbiosis and an ideal system for understanding antibiotic deployment in an ecological context. We found that Pseudonocardia symbionts of the ant Trachymyrmex septentrionalis have strong antibiotic activity against their most likely competitors: other strains of ant-associated bacteria. Activity-guided fractionation revealed the defensive molecule produced by these bacteria to be the thiopeptide antibiotic GE37468. Here we assign an ecological role – host-associated niche defense – for this antibiotic, previously identified in a biochemical screen and known only for its in vitro activity against clinically-relevant pathogens. Genomic analysis uncovered a split biosynthetic gene cluster for this molecule and suggests that these symbionts acquired it from soil bacteria. Similar thiopeptide antibiotics have recently been ascribed host-associated niche defense roles, and the function of GE37468 in this insect niche intriguingly parallels thiopeptide defense in the human microbiome. Molecular defenses from animal-associated microbes may have particular promise as therapeutics, and indeed thiopeptide antibiotics with high structural similarity to GE37468 are already under clinical investigation.

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A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes

Cited by 26 publications

References 32 publications

RiPP antibiotics: biosynthesis and engineering potential

RiPP antibiotics: biosynthesis and engineering potential

Conformational Response of 30S-bound IF3 to A-Site Binders Streptomycin and Kanamycin

Thiopeptide Defense by an Ant’s Bacterial Symbiont

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