High-resolution crystal structures of ribosome-bound chloramphenicol and erythromycin provide the ultimate basis for their competition

Svetlov, Maxim S.; Plessa, Elena; Chen, Chih-Wei; Bougas, Anthony; Krokidis, Marios G.; Dinos, George P.; Polikanov, Yury S.

doi:10.1261/rna.069260.118

Cited by 56 publications

(77 citation statements)

References 32 publications

(48 reference statements)

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“…(B to D) Occlusion of the nascent peptide exit tunnel by DIR, ERY, and TEL. Structures of ERY and TEL are from PDB entries 6ND6 (35) and 4X7Z (4), respectively. Note that the side chain of DIR forms LP-stacking interaction with the His69 residue of the ribosomal protein uL4.…”

Section: Resultsmentioning

confidence: 99%

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Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides

Khabibullina

Tereshchenkov

Komarova

et al. 2019

Antimicrob Agents Chemother

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Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chemical moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-methyl side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pairstacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.

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Section: Resultsmentioning

confidence: 99%

“…The E-site tRNA is omitted for clarity. (B) Superposition of ribosome-bound DIR (yellow) with ERY (red) (PDB accession number 6ND6[35]) and TEL (magenta) (PDB entry 4V7Z[4]). All structures were aligned based on domain V of the 23S rRNA.…”

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confidence: 99%

Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides

Khabibullina

Tereshchenkov

Komarova

et al. 2019

Antimicrob Agents Chemother

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“…As the inhibition occurs directly after initiation of protein synthesis, the nascent polypeptide chain remains short, however, the length size is determined by binding of the macrolide structure to the complex. Consequently, the size and conformation of erythromycin play a crucial role in the bioactivity of the molecule [66]. In case of erythromycin A, binding to the 50S subunit leads to dissociation and accumulation of peptidyl-tRNAs with six, seven, or eight amino acid residues.…”

Section: Erythromycin and Derivativesmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

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“…Following the analogy with KLB, we proposed that PHZ acts upon the bacterial ribosome. To determine the exact mechanism of translation inhibition by PHZ we attempted to crystallize the 70S ribosome from Thermus thermophilus (Tth) in complex with PHZ, mRNA, and tRNAs, as previously done with KLB 8 , and several other translation inhibitors [23][24][25][26][27][28][29][30] . Despite numerous attempts, we were not able to observe any positive electron density peaks corresponding to the ribosome-bound PHZ anywhere within the Tth 70S ribosome.…”

Section: Phz Obstructs the Nascent Peptide Exit Tunnel Of The Ribosomementioning

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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High-resolution crystal structures of ribosome-bound chloramphenicol and erythromycin provide the ultimate basis for their competition

Cited by 56 publications

References 32 publications

Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides

Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

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

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