Conformations in solution and bound to bacterial ribosomes of ketolides, HMR 3647 (telithromycin) and RU 72366: A new class of highly potent antibacterials

Evrard‐Todeschi, Nathalie; Gharbi-Benarous, Josyane; Gaillet, Christine; Verdier, Laurent; Bertho, Gildas; Lang, Catherine; Parent, Annick; Girault, Jean‐Pierre

doi:10.1016/s0968-0896(00)00091-2

Cited by 22 publications

(14 citation statements)

References 41 publications

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“…Signs for conformational alteration were observed upon comparison of the NMR data obtained in chloroform to that in methanol and solution ensembles were proposed, but with limited certainty . The conformation of telithromycin in aqueous solution has been analysed based on the δ , J , T 1 data and NOEs in combination with restrained MD calculations, providing helpful insights into the flexibility and geometry of the macrocycle, yet without being able to describe the composition of the solution ensemble . The NMR assignment of spiramycin has been published, but its conformational ensembles have not been described .…”

Section: Resultsmentioning

confidence: 99%

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

Danelius

Poongavanam

Peintner

et al. 2020

Chemistry A European J

212

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It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behavea smolecular chameleons to combine otherwisec onflicting properties, including aqueous solubility,c ell permeability and target binding. Evidence for this has, however,b een limited to the cyclic peptidec yclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing al ess pronounced behaviour.I n particular roxithromycin, telithromycin and spiramycin display am arked, yet limited flexibility and populate signifi-cantly less polar and more compact conformational ensembles in an apolart han in ap olar environment. In addition to balancingo fm embrane permeability and aqueous solubility, this flexibility also allows binding to targetst hat vary in structure between species. The drugs' passivec ell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability,d eveloped for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.[a] Dr.

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Section: Resultsmentioning

confidence: 99%

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

Danelius

Poongavanam

Peintner

et al. 2020

Chemistry A European J

212

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“…In order to optimize therapeutic activities against both sensitive and resistant respiratory pathogenic bacteria, another chemical variation consisted in replacing the methyl initially present on the C10 or C12 carbon of ketolides with non-polar groups [147] [154] [155]. The aim of such an option was to keep in ketolides series, the same overall hydrophobic character observed at the level of the underside of the neomacrolide macrocycle [156] [157] [158] [159]; which could lead to new ketolides with an antibacterial spectrum and more effective pharmacokinetic properties. The pharmacomodulation undertaken consisted in replacing methyl in C12 by a vinyl-like group [154] or to introduce in addition on C10, a hydroxyl [147] or also in replacing methyl in C10 by an alkylamine group [155].…”

Section: C10 and C12-substituted Ketolidesmentioning

confidence: 99%

Pharmacochemical Aspects of the Evolution from Erythromycin to Neomacrolides, Ketolides and Neoketolides

Ouattara¹,

Songuigama²,

Jean-Paul³

2020

OJMC

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Antibiotic macrolides are experiencing renewed interest in anti-infective therapy since the advent of ketolides. This therapeutic class was introduced in order to broaden the narrow antibacterial spectrum of macrolides and to cope with the emergence of germs resistant to Erythromycin A and its hemisynthetic derivatives or neomacrolides (Clarithromycin, Roxithromycin, Azithromycin, Dirithromycin). From a pharmacochemical point of view, ketolides were first of all obtained by operating chemical modulations on Erythromycin A to obtain the neomacrolides, then, by replacing the neutral sugar (L-cladinose) in C3 by a ketone function coupled with the creation of an oxazolidinone like heterocycle in C11 and C12 in place of the hydroxyls present in these positions (Telithromycin, Cethromycin, Solithromycin). These modulations have enabled the improvement of the chemical stability of ketolides in gastric acid medium and increase their affinity for the ribosomal target, hence the broadening of their spectrum of action towards Gram positive germs including strains resistant to other macrolides and to neomacrolides. Therefore, the objective of this systematic review is to report the various pharmacochemical aspects undertaken since 1952 in the macrolide series based on the structure of Erythromycin A. These aspects will focus on the pharmacomodulations that have led, year after year, to the optimization of stability, the improvement of the pharmacodynamic and pharmacokinetic profile and that have allowed the development of neomacrolides, ketolides and neoketolides, which are today essential in the management of severe bronchopulmonary infections.

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“…Concept of combining active macrolide scaffold and (hetero) aromatic unit via a flexible linker resulted with compounds showing remarkable antibacterial activity. This effect was first recognized in the ketolide group of macrolide antibiotics, where the cladinose sugar is substituted with a keto-group, with a cyclic carbamate group attached in the lactone ring, with telithromycin ( Figure 3 ) [ 29 , 70 , 71 , 72 , 73 ]. These modifications enable ketolides to become more active on a much broader spectrum than other macrolides [ 70 ].…”

Section: New Macrocyclic Ribosome Inhibitors As Possible Way To Avmentioning

confidence: 99%

From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials

2016

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Macrolides, as a class of natural or semisynthetic products, express their antibacterial activity primarily by reversible binding to the bacterial 50S ribosomal subunits and by blocking nascent proteins’ progression through their exit tunnel in bacterial protein biosynthesis. Generally considered to be bacteriostatic, they may also be bactericidal at higher doses. The discovery of azithromycin from the class of macrolides, as one of the most important new drugs of the 20th century, is presented as an example of a rational medicinal chemistry approach to drug design, applying classical structure-activity relationship that will illustrate an impressive drug discovery success story. However, the microorganisms have developed several mechanisms to acquire resistance to antibiotics, including macrolide antibiotics. The primary mechanism for acquiring bacterial resistance to macrolides is a mutation of one or more nucleotides from the binding site. Although azithromycin is reported to show different, two-step process of the inhibition of ribosome function of some species, more detailed elaboration of that specific mode of action is needed. New macrocyclic derivatives, which could be more potent and less prone to escape bacterial resistance mechanisms, are also continuously evaluated. A novel class of antibiotic compounds—macrolones, which are derived from macrolides and comprise macrocyclic moiety, linker, and either free or esterified quinolone 3-carboxylic group, show excellent antibacterial potency towards key erythromycin-resistant Gram-positive and Gram-negative bacterial strains, with possibly decreased potential of bacterial resistance to macrolides.

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Conformations in solution and bound to bacterial ribosomes of ketolides, HMR 3647 (telithromycin) and RU 72366: A new class of highly potent antibacterials

Cited by 22 publications

References 41 publications

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

Pharmacochemical Aspects of the Evolution from Erythromycin to Neomacrolides, Ketolides and Neoketolides

From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials

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