Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel

Metelev, Mikhail; Osterman, Ilya А.; Ghilarov, Dmitry; Khabibullina, Nelli F; Yakimov, Alexander; Shabalin, Konstantin A.; Уткина, И. И.; Travin, Dmitrii Y.; Komarova, Ekaterina S.; Serebryakova, Marina V.; Артамонова, Т. О.; Khodorkovskii, M. A.; Konevega, Andrey L.; Сергиев, Петр В.; Severinov, Konstantin; Polikanov, Y.S.

doi:10.1038/nchembio.2462

Cited by 59 publications

(75 citation statements)

References 55 publications

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“…Several examples of natural peptides in the PDB contain dehydroamino acids including Thiostrepton (PDB ID 5d8h), Largazole (PDB ID 3rqd), and Klebsazolicin (PDB ID 5w4k). Structural and functional implications of incorporating α,β‐dehydroamino acids are discussed here, for three classes of functional molecules: antibiotics, anticancer agents, and enzyme inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

2018

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Extensive efforts invested in understanding the rules of protein folding are now being applied, with good effect, in de novo design of proteins/peptides. For proteins containing standard α‐amino acids alone, knowledge derived from experimentally determined three‐dimensional (3D) structures of proteins and biologically active peptides are available from the Protein Data Bank (PDB), and the Cambridge Structural Database (CSD). These help predict and design protein structures, with reasonable confidence. However, our knowledge of 3D structures of biomolecules containing backbone modified amino acids is still evolving. A major challenge in de novo protein/peptide design concerns the engineering of conformationally constrained molecules with specific structural elements and chemical groups appropriately positioned for biological activity. This review explores four classes of amino acid modifications that constrain protein/peptide backbone structure. Systematic analysis of peptidic molecule structures (eg, bioactive peptides, inhibitors, antibiotics, and designed molecules), containing these backbone‐modified amino acids, found in the PDB and CSD are discussed. The review aims to provide structure–function insights that will guide future design of proteins/peptides.

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Section: Resultsmentioning

confidence: 99%

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

2018

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“…nascent peptide (Metelev et al, 2017). Proline-rich antimicrobial peptides (PrAMPs) have been found in insects, crustaceans, and mammals.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

From Worms to Drug Candidate: The Story of Odilorhabdins, a New Class of Antimicrobial Agents

Racine

Gualtieri

2019

Front. Microbiol.

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A major issue currently facing medicine is antibiotic resistance. No new class of antibiotics for the treatment of Gram-negative infections has been introduced in more than 40 years. We screened a collection of Xenorhabdus and Photorhabdus strains in the quest to discover new structures that are active against the most problematic multidrug-resistant bacteria. These species are symbiotic bacteria of entomopathogenic nematodes and their life cycle, the richness of the bacteria's genome in non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) genes, and their propensity to produce secondary metabolites with a large diversity of chemical structures make them a good starting point to begin an ambitious drug discovery program. Odilorhabdins (ODLs), a novel antibacterial class, were identified from this campaign. These compounds inhibit bacterial translation by binding to the small ribosomal subunit at a site not exploited by current antibiotics. Following the development of the total synthesis of this family of peptides, a medicinal chemistry program was started to optimize their pharmacological properties. NOSO-502, the first ODL preclinical candidate was selected. This compound is currently under preclinical development for the treatment of multidrug-resistant Gram-negative infections in hospitalized patients.

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“…Reverse-phase HPLC analysis of medium after cultivation of the Rhizobium sp. Pop5 led to the identification of several fractions absorbing at 254 nm, a wavelength previously used in the purification of other azole-containing compounds (Figure S1A) 8,13 . MALDI-TOF-MS analysis of the selected fractions showed the presence of compounds, which, based on the observed masses, appeared to be the products of the PhzA precursor peptide posttranslational modification Figure S3).…”

Section: Purification and Characterization Of A New Lapmentioning

confidence: 99%

“…Although less than two dozens of LAPs can be considered as well-characterized, they demonstrate antibacterial activity through several completely different mechanisms. For example, microcin B17 is a DNAgyrase poison 6 , plantazolicin targets the membrane 7 , and klebsazolicin inhibits the ribosome 8 .…”

Section: Introductionmentioning

confidence: 99%

Phazolicin – a Novel Thiazole/Oxazole-Modified Peptide Inhibiting the Bacterial Ribosome in a Species-Specific Way

Travin

Watson

Metelev

et al. 2019

Preprint

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Y.S.P.). Travin D.Y. et al. Manuscript P a g e | 2 of 32 ABSTRACT Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly expanding and largely untapped class of natural products with various biological activities. Linear azol(in)e-containing peptides (LAPs) comprise a subclass of RiPPs that display an outstanding diversity of mechanisms of action while sharing common structural features. Here, we report the discovery of a new LAP biosynthetic gene cluster in the genome of Rhizobium sp.Pop5, which encodes the precursor peptide and modification machinery of phazolicin (PHZ)an extensively modified peptide exhibiting narrow-spectrum antibacterial activity against some symbiotic bacteria of leguminous plants belonging to the Rhizobiales. PHZ inhibits prokaryotic translation through the obstruction of the passage of the nascent peptide through the ribosome exit channel. The cryo-EM structure of the Escherichia coli ribosome with bound PHZ revealed that the drug interacts with the 23S rRNA and ribosomal proteins uL4 and uL22 and obstructs the exit tunnel in a way that is distinct from other compounds blocking the exit channel. Weshow that the sequence of uL4 ribosomal protein loop involved in PHZ binding determines the species-specificity of antibiotic interaction with its target. PHZ and its predicted homologs from other bacterial species expand the known diversity of LAPs and may be used in the future as biocontrol agents for the needs of agriculture.

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Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel

Cited by 59 publications

References 55 publications

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

From Worms to Drug Candidate: The Story of Odilorhabdins, a New Class of Antimicrobial Agents

Phazolicin – a Novel Thiazole/Oxazole-Modified Peptide Inhibiting the Bacterial Ribosome in a Species-Specific Way

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