Drugs of the 21st century: telithromycin (HMR 3647)--the first ketolide

Ackermann, Grit; Rodloff, Arne C.

doi:10.1093/jac/dkg123

Cited by 113 publications

(68 citation statements)

References 71 publications

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“…Subsequently, modifications in the macrolide basal structure led to the development of new subgroups of macrolides such as the azalides, with azithromycin being the first and most representative member (Mutak, 2007), or ketolides such as telithromycin (Ackermann & Rodloff, 2003;Zuckerman, 2004) (Figure 1). New antibiotic macrolides with other number of carbon atoms (e.g.…”

Section: Historymentioning

confidence: 99%

“…the number of carbon atoms in the macrolactonic ring (Table 1 and Figure 2). Regarding structural modifications, four different classes have been described: those classically referred to as macrolides, such as erythromycin, which were the molecules first described; azalides, like azithromycin, that incorporate a nitrogen in the macrolactonic ring resulting in higher basicity and increasing both acid stability and bioavailability (Mutak, 2007); and ketolides, which possess a keto group at the C3 position of the lactone ring instead of the cladinose sugar found in erythromycin, enhancing their activity spectrum and improving their acid stability, and of which telithromycin is a representative class member (Ackermann & Rodloff, 2003;Schl€ unzen et al, 2003;Zhanel et al, 2002); finally, ketolides such as solithromycin, which incorporate a fluor atom in C2 (fluoroketolides), are currently under development (Llano-Sotelo et al, 2010;Putnam et al, 2010). Additionally, subclasses such as triamilides, which are represented by tulatrhomycin, a tribasic derivative azalide, have also been proposed (Letavic et al, 2002).…”

Section: Structure and Classificationmentioning

confidence: 99%

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Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Gomes

Martínez-Puchol

Palma

et al. 2016

Critical Reviews in Microbiology

119

120

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Section: Historymentioning

confidence: 99%

Section: Structure and Classificationmentioning

confidence: 99%

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Gomes

Martínez-Puchol

Palma

et al. 2016

Critical Reviews in Microbiology

119

120

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“…Ketolides present yet another chemical approach based on the addition of rather long extensions, such as alkyl-aryl or quinollyallyl, to the core macrolactone ring; this approach is expected to provide additional interactions, thus minimizing the contribution of 2058-2059 region. The macrolactone ring of the ketolide is characterized by the presence of a keto group instead of the cladinose sugar at its C3 position, an 11,12-cyclic carbamate (76)(77)(78)(79)(80)(81)(82)(83).…”

Section: Typical Macrolidesmentioning

confidence: 99%

ANTIBIOTICS TARGETING RIBOSOMES: Resistance, Selectivity, Synergism, and Cellular Regulation

Yonath

2005

Annu. Rev. Biochem.

206

145

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Key Words ribosomal crystallography, peptide-bond formation, antibiotic synergism, nascent protein exit tunnel ■ Abstract Antibiotics target ribosomes at distinct locations within functionally relevant sites. They exert their inhibitory action by diverse modes, including competing with substrate binding, interfering with ribosomal dynamics, minimizing ribosomal mobility, facilitating miscoding, hampering the progression of the mRNA chain, and blocking the nascent protein exit tunnel. Although the ribosomes are highly conserved organelles, they possess subtle sequence and/or conformational variations. These enable drug selectivity, thus facilitating clinical usage. The structural implications of these differences were deciphered by comparisons of high-resolution structures of complexes of antibiotics with ribosomal particles from eubacteria resembling pathogens and from an archaeon that shares properties with eukaryotes. The various antibiotic-binding modes detected in these structures demonstrate that members of antibiotic families possessing common chemical elements with minute differences might bind to ribosomal pockets in significantly different modes, governed by their chemical properties.

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“…These and other modifications improve the stability of ketolides in acidic environments, prevent the induction of MLS B resistance, and maintain activity against organisms that develop inducible resistance to MLS B antimicrobials (2). Mechanisms that confer resistance to MLS B antimicrobials include target site modification and active antimicrobial efflux (1). Target site modification is encoded by constitutive or inducible erm genes (16) that may require exposure to subinhibitory concentrations of erythromycin for optimal expression (18).…”

mentioning

confidence: 99%

Induction of Telithromycin Resistance by Erythromycin in Isolates of Macrolide-Resistant Staphylococcus spp

Davis

Crawford

Fiebelkorn

et al. 2005

Antimicrob Agents Chemother

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Staphylococcal isolates were examined for possible macrolide-inducible resistance to telithromycin. All macrolide-resistant isolates demonstrated telithromycin D-shaped zones. This result did not discriminate between resistance due to an efflux mechanism (msrA) or a ribosomal target modification (ermA or ermC). Inducible telithromycin resistance in staphylococci does not appear to be analogous to inducible clindamycin resistance.Telithromycin is the first commercially available ketolide. Ketolides are a recently developed class of antimicrobial agents that belong to the macrolide-lincosamide-streptogramin B (MLS B ) family. Ketolides possess significant structural differences from macrolides, including a second site of interaction with the ribosome at domain II on the 23S rRNA of the 50S ribosomal subunit (4). This is in addition to the interaction at domain V, which is where 14-and 15-membered-ring macrolides act (2). These and other modifications improve the stability of ketolides in acidic environments, prevent the induction of MLS B resistance, and maintain activity against organisms that develop inducible resistance to MLS B antimicrobials (2). Mechanisms that confer resistance to MLS B antimicrobials include target site modification and active antimicrobial efflux (1). Target site modification is encoded by constitutive or inducible erm genes (16) that may require exposure to subinhibitory concentrations of erythromycin for optimal expression (18). The active antimicrobial efflux pumps that have been described for Staphylococcus aureus are encoded by the msrA, msrB, and NorA genes (11, 16).We previously reported a practical disk approximation method which identified 97% of S. aureus strains and 100% of coagulase-negative staphylococcus (CoNS) strains with inducible MLS B resistance during routine disk diffusion susceptibility testing (6). A similar method involves placing erythromycin and clindamycin disks in close proximity on standard sheep blood agar plates used for verification of inoculum purity when broth-based susceptibility tests are performed (10). These tests are intended to detect strains with inducible MLS B resistance in order to avoid potential clinical failures with clindamycin therapy (5,7,15,17). The goal of the present study was to determine if inducible telithromycin resistance, like inducible clindamycin resistance, might occur in macrolide-resistant staphylococci.A group of 100 S. aureus clinical isolates and 100 CoNS clinical isolates, some of which have been previously described (6), were selected for study. All isolates were macrolide resistant by standard Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) disk diffusion testing (14). An additional 10 S. aureus isolates that were susceptible to erythromycin were included. Standard CLSI disk diffusion testing (14) was performed on all isolates by use of Mueller-Hinton agar (Becton-Dickinson Microbiology Systems, Cockeysville, MD) with standard 15-g erythromycin disks, 2-g clindamycin disks, and 15-g telithromycin disk...

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Drugs of the 21st century: telithromycin (HMR 3647)--the first ketolide

Cited by 113 publications

References 71 publications

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

ANTIBIOTICS TARGETING RIBOSOMES: Resistance, Selectivity, Synergism, and Cellular Regulation

Induction of Telithromycin Resistance by Erythromycin in Isolates of Macrolide-Resistant Staphylococcus spp

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