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Champney, W. Scott; Tober, Craig L.

doi:10.1007/s002840010205

Cited by 13 publications

(14 citation statements)

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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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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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“…It should also be noted that Evn has also been shown to inhibit specifically assembly of the 50S subunit. However, this assembly inhibition required a 50% inhibitory dose some 10 times higher than that required to inhibit protein synthesis indicating that ribosome function is the primary target of the drug [42]. There are numerous antibiotics that are much more efficient inhibitors of ribosome assembly and they are the subject of the next section.…”

Section: Evernimicin and Avilamycinmentioning

confidence: 99%

“…[43]). In the past few years the list has been growing rapidly and now includes representatives of the entire MLSB class of 50S subunit inhibitors, i.e., macrolides, lincosamides and streptogramin B compounds [42], as well as many antibiotics that target the 30S subunit, such as members of the aminoglycoside family [44]. A number of clinical relevant antibiotics fall into these categories [107]).…”

Section: Antibiotic Inhibitors Of Ribosome Assemblymentioning

confidence: 99%

Antibiotics and the Inhibition of Ribosome Function

Wilson

2004

Protein Synthesis and Ribosome Structure

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“…In consequence, termination is also affected by both lincomycin and clindamycin (12). In addition to the inhibitory effect on protein synthesis, each lincosamide exhibits a specific inhibitory effect on the 50 S-subunit formation, an activity shared with 16-membered macrolide and streptogramin B antibiotics (13).…”

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confidence: 99%

Unraveling New Features of Clindamycin Interaction with Functional Ribosomes and Dependence of the Drug Potency on Polyamines

Kouvela

Πετρόπουλος

Kalpaxis

2006

Journal of Biological Chemistry

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The effect of spermine on the inhibition of peptide-bond formation by clindamycin, an antibiotic of the Macrolide-Lincosamide-Streptogramins B family, was investigated in a cell-free system derived from Escherichia coli. In this system peptide bond is formed between puromycin, a pseudo-substrate of the A-site, and acetylphenylalanyl-tRNA, bound at the P-site of poly(U)-programmed 70 S ribosomes. Biphasic kinetics revealed that one molecule of clindamycin, after a transient interference with the A-site of ribosomes, is slowly accommodated near the P-site and perturbs the 70 S/acetylphenylalanyl-tRNA complex so that a peptide bond is still formed but with a lower velocity compared with that observed in the absence of the drug. The above mechanism requires a high temperature (25°C as opposed to 5°C). If this is not met, the inhibition is simple competitive. It was found that at 25°C spermine favors the clindamycin binding to ribosomes; the affinity of clindamycin for the A-site becomes 5 times higher, whereas the overall inhibition constant undergoes a 3-fold decrease. Similar results were obtained when ribosomes labeled with N 1 -azidobenzamidinospermine, a photo-reactive analogue of spermine, were used or when a mixture of spermine and spermidine was added in the reaction mixture instead of spermine alone. Polyamines cannot compensate for the loss of biphasic kinetics at 5°C nor can they stimulate the clindamycin binding to ribosomes. Our kinetic results correlate well with photoaffinity labeling data, suggesting that at 25°C polyamines bound at the vicinity of the drug binding pocket affect the tertiary structure of ribosomes and influence their interaction with clindamycin.Lincomycin and clindamycin ( Fig. 1) are lincosamides, still used as therapeutic agents in human diseases and some animal infections. Clindamycin, a semisynthetic derivative of lincomycin (7(S)-chloro-7-deoxylincomycin), is usually more active than the parent compound in the treatment of bacterial infections, in particular those caused by anaerobic species (1).Lincosamides act on the large ribosomal subunit and share an overlapping binding site with macrolides, streptogramins B, chloramphenicol, and other antibiotics affecting the PTase 2 center, as deduced from competition experiments and crossresistance data (for review, see Ref.2) as well as from twodimensional transferred nuclear Overhauser effect spectroscopy analysis (3). In agreement with most of these observations, chemical footprinting analysis (4, 5) and crystallographic studies (6, 7) have revealed that lincosamides interact with both the A-site and the P-site on the 50 S ribosomal subunit and would be expected to hamper the positioning of aminoacyl moieties of tRNAs at both sites. This last view is consistent with earlier binding studies investigating the competition for binding to ribosomes between lincomycin and 3Ј-terminus pentanucleotide fragments from N-AcLeu-tRNA Leu , Leu-tRNA Leu , and Phe-tRNA Phe (8, 9) as well as with the finding that lincosamides stimulate oligopeptidy...

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Cited by 13 publications

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

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

Antibiotics and the Inhibition of Ribosome Function

Unraveling New Features of Clindamycin Interaction with Functional Ribosomes and Dependence of the Drug Potency on Polyamines

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