Development of Genetically Encoded Biosensors for Reporting the Methyltransferase-Dependent Biosynthesis of Semisynthetic Macrolide Antibiotics

: As a kind of haemoglobin, cytochrome P450 enzymes (CYP450) participate in the metabolism of many substances, including endogenous substances, exogenous substances and drugs. It is estimated that 60% of common prescription drugs require bioconversion through CYP450. The influence of macrolides on CYP450 contributes to the metabolism and drug-drug interactions (DDIs) of macrolides. At present, most studies on the effects of macrolides on CYP450 are focused on CYP3A, but a few exist on other enzymes and drug combinations, such as telithromycin, which can decrease the activity of hepatic CYP1A2 and CYP3A2. This article summarizes some published applications of the influence of macrolides on CYP450 and the DDIs of macrolides caused by CYP450. And the article may subsequently guide the rational use of drugs in clinical trials. To a certain extent, poisoning caused by adverse drug interactions can be avoided. Unreasonable use of macrolide antibiotics may enable the presence of residue of macrolide antibiotics in animal-origin food. It is unhealthy for people to eat food with macrolide antibiotic residues. So it is of great significance to guarantee food safety and protect the health of consumers by the rational use of macrolides. This review gives a detailed description of the influence of macrolides on CYP450 and the DDIs of macrolides caused by CYP450. Moreover, it offers a perspective for researchers to further explore in this area.

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Chemistry and Biology of the Polyene Macrolide Antibiotics

Bacteriological Reviews ◽

10.1128/mmbr.37.3.407-407.1973 ◽

1973 ◽

Vol 37 (3) ◽

pp. 407-407

Keyword(s):

Macrolide Antibiotics ◽

Polyene Macrolide ◽

Polyene Macrolide Antibiotics

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Considerations for and Mechanisms of Adjunct Therapy in COPD

Journal of Clinical Medicine ◽

10.3390/jcm10061225 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1225

Author(s):

Rachana Mandru ◽

Christine Y. Zhou ◽

Rachel Pauley ◽

Robert M. Burkes

Keyword(s):

Vitamin D ◽

Adverse Events ◽

Hypertonic Saline ◽

Clinical Data ◽

Therapeutic Approach ◽

Vitamin D Supplementation ◽

Review Article ◽

Macrolide Antibiotics ◽

Oral Corticosteroids ◽

Expert Recommendations

Inhaled bronchodilators and corticosteroids, when indicated, form the backbone of COPD therapy. However, over the last decade there has been an emergence of adjunct therapies in oral or inhaled form that are now part of the therapeutic approach to COPD. While these therapies have shown to be beneficial when used in the appropriate instances, there are particular considerations that need to be minded when using these therapies. This review article discussed the mechanism of roflumilast, macrolide antibiotics, other chronic antibiotic regimens, vitamin D supplementation, oral corticosteroids, n-acetylcysteine, and nebulized hypertonic saline, the clinical data behind each of these therapies, adverse events associated with therapy, and the expert recommendations for their utilization. Our goal is to provide a brief but informative and clinically useful review of commonly encountered therapies used in advanced COPD.

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Context-specific action of macrolide antibiotics on the eukaryotic ribosome

Nature Communications ◽

10.1038/s41467-021-23068-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Maxim S. Svetlov ◽

Timm O. Koller ◽

Sezen Meydan ◽

Vaishnavi Shankar ◽

Dorota Klepacki ◽

...

Keyword(s):

Amino Acid Sequences ◽

Macrolide Antibiotics ◽

Single Mutation ◽

Sequence Motifs ◽

Eukaryotic Translation ◽

Eukaryotic Ribosome ◽

Cellular Translation ◽

Distinct Sequence ◽

Exit Tunnel ◽

Context Specific

AbstractMacrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Cryo-EM structural analysis showed that the macrolide telithromycin binds in the tunnel of the engineered eukaryotic ribosome. Genome-wide analysis of cellular translation and biochemical studies demonstrated that the drug inhibits eukaryotic translation by preferentially stalling ribosomes at distinct sequence motifs. Context-specific action markedly depends on the macrolide structure. Eliminating macrolide-arrest motifs from a protein renders its translation macrolide-tolerant. Our data illuminate the prospects of adapting macrolides for protein-selective translation inhibition in eukaryotic cells.

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Macrolide antibiotics inhibit the degradation of the glucocorticoid-responsive cytochrome P-450p in rat hepatocytes in vivo and in primary monolayer culture.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)84558-1 ◽

1986 ◽

Vol 261 (14) ◽

pp. 6264-6271

Author(s):

P B Watkins ◽

S A Wrighton ◽

E G Schuetz ◽

P Maurel ◽

P S Guzelian

Keyword(s):

Monolayer Culture ◽

Rat Hepatocytes ◽

Macrolide Antibiotics ◽

Primary Monolayer Culture ◽

Primary Monolayer

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Fate of Macrolide Antibiotics with Different Wastewater Treatment Technologies

Water Air & Soil Pollution ◽

10.1007/s11270-021-05053-y ◽

2021 ◽

Vol 232 (3) ◽

Author(s):

Min Pan ◽

Pui Ching Yau

Keyword(s):

Wastewater Treatment ◽

Macrolide Antibiotics ◽

Treatment Technologies

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Binding Site of the Bridged Macrolides in the Escherichia coli Ribosome

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.1.281-288.2005 ◽

2005 ◽

Vol 49 (1) ◽

pp. 281-288 ◽

Cited By ~ 45

Author(s):

Liqun Xiong ◽

Yakov Korkhin ◽

Alexander S. Mankin

Keyword(s):

Escherichia Coli ◽

Tight Binding ◽

Dimethyl Sulfate ◽

23S Rrna ◽

Side Chain ◽

Macrolide Antibiotics ◽

Side Chains ◽

Alkyl Aryl ◽

E Coli ◽

Exit Tunnel

ABSTRACT Ketolides represent the latest group of macrolide antibiotics. Tight binding of ketolides to the ribosome appears to correlate with the presence of an extended alkyl-aryl side chain. Recently developed 6,11-bridged bicyclic ketolides extend the spectrum of platforms used to generate new potent macrolides with extended alkyl-aryl side chains. The purpose of the present study was to characterize the site of binding and the action of bridged macrolides in the ribosomes of Escherichia coli. All the bridged macrolides investigated efficiently protected A2058 and A2059 in domain V of 23S rRNA from modification by dimethyl sulfate and U2609 from modification by carbodiimide. In addition, bridged macrolides that carry extended alkyl-aryl side chains protruding from the 6,11 bridge protected A752 in helix 35 of domain II of 23S rRNA from modification by dimethyl sulfate. Bridged macrolides efficiently displaced erythromycin from the ribosome in a competition binding assay. The A2058G mutation in 23S rRNA conferred resistance to the bridged macrolides. The U2609C mutation, which renders E. coli resistant to the previously studied ketolides telithromycin and cethromycin, barely affected cell susceptibility to the bridged macrolides used in this study. The results of the biochemical and genetic studies indicate that in the E. coli ribosome, bridged macrolides bind in the nascent peptide exit tunnel at the site previously described for other macrolide antibiotics. The presence of the side chain promotes the formation of specific interactions with the helix 35 of 23S rRNA.

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