Recent Advances in the Medicinal Chemistry of Novel Erythromycin- Derivatized Antibiotics

Ying, Lu; Tang, Datong

doi:10.2174/156802610792232042

Cited by 19 publications

(7 citation statements)

References 48 publications

(51 reference statements)

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“…1A), was discovered in 1952 (7). Due to its efficiency against a broad spectrum of bacterial pathogens and to its safety, it was introduced into the clinic in the same year (8). However, ERY is not stable and easily degrades under the acidic conditions in the stomach.…”

mentioning

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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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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mentioning

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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“…The development of novel erythromycin-based antibiotics has been a much-researched area since the seventies. The outcome of such persistent efforts has resulted in beneficial drugs like clarithromycin, azithromycin, dirithromycin, roxithromycin, fluorithromycin, and telithromycin (61). The macrolide antibiotics erythromycin, clarithromycin, and roxithromycin have proven to be effective as long-term treatment for the idiopathic, Asian-prevalent lung disease diffuse panbronchiolitis (DPB), (62).…”

Section: Erythromycinmentioning

confidence: 99%

Antibacterial Agents from Actinomycetes - A Review

Mahajan¹

2012

Front Biosci

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“…This has led to the development of a new generation of macrolides, namely, ketolides, with the most distinguished members being telithromycin, cethromycin, and solithromycin ( Fig. 1B to D) (7,(10)(11)(12)(13). These ketolides are semisynthetic derivatives of erythromycin, where a keto group at the C-3 position of the lactone ring replaces the cladinose sugar present in erythromycin.…”

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confidence: 99%

Insights into the Mode of Action of Novel Fluoroketolides, Potent Inhibitors of Bacterial Protein Synthesis

Krokidis

Márquez

Wilson

et al. 2014

Antimicrob Agents Chemother

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Ketolides, the third generation of expanded-spectrum macrolides, have in the last years become a successful weapon in the endless war against macrolide-resistant pathogens. Ketolides are semisynthetic derivatives of the naturally produced macrolide erythromycin, displaying not only improved activity against some erythromycin-resistant strains but also increased bactericidal activity as well as inhibitory effects at lower drug concentrations. In this study, we present a series of novel ketolides carrying alkyl-aryl side chains at the C-6 position of the lactone ring and, additionally, one or two fluorine atoms attached either directly to the lactone ring at the C-2 position or indirectly via the C-13 position. According to our genetic and biochemical studies, these novel ketolides occupy the known macrolide binding site at the entrance of the ribosomal tunnel and exhibit lower MIC values against wild-type or mutant strains than erythromycin. In most cases, the ketolides display activities comparable to or better than the clinically used ketolide telithromycin. Chemical protection experiments using Escherichia coli ribosomes bearing U2609C or U754A mutations in 23S rRNA suggest that the alkylaryl side chain establishes an interaction with the U2609-A752 base pair, analogous to that observed with telithromycin but unlike the interactions formed by cethromycin. These findings reemphasize the versatility of the alkyl-aryl side chains with respect to species specificity, which will be important for future design of improved antimicrobial agents.

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Recent Advances in the Medicinal Chemistry of Novel Erythromycin- Derivatized Antibiotics

Cited by 19 publications

References 48 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

Antibacterial Agents from Actinomycetes - A Review

Insights into the Mode of Action of Novel Fluoroketolides, Potent Inhibitors of Bacterial Protein Synthesis

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