Peptide derivatives of tylosin-related macrolides

Коршунова, Г. А.; Sumbatyan, N. V.; Fedorova, N. V.; Кузнецова, И. В.; Shishkina, A. V.; Bøgdanov, A.

doi:10.1134/s1068162007020033

Cited by 4 publications

(4 citation statements)

References 16 publications

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“…OMT was obtained by acidic hydrolysis of tylosin as described earlier . Our strategy of the preparation of OMT peptide derivatives was partially developed in the previous study . In the case of OMT derivatives bearing Trp this approach allowed a relatively simple synthesis (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…The preparation method for the C23 derivatives of OMT, which was developed in our previous research and refined in this study, allowed us to synthesize in satisfactory yields a series of compounds with Trp residues located at different distances from the tylonolide ring. Although no crystal structure of a complex of OMT with the ribosome is available it was conclusively demonstrated that the lactone rings of tylosin and OMT are similarly positioned in NPET .…”

Section: Discussionmentioning

confidence: 99%

“…With this goal in mind, we have previously designed and prepared a number of tylosin (Figure , 1 ), desmycosin, and 5- O -mycominosyltylonolide (OMT) (Figure , 2 ) peptide derivatives. − The peptide portion of these molecules models elements of a growing polypeptide chain, whereas the antibiotic part serves as an ″anchor″ for positioning the peptide at a specific site of NPET. In particular, it was shown that amino acids and peptides attached to the C20 aldehyde position of tylosin could be useful instruments for monitoring the first (next to PTC) regulatory region of NPET …”

Section: Introductionmentioning

confidence: 99%

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Conjugates of Amino Acids and Peptides with 5-O-Mycaminosyltylonolide and Their Interaction with the Ribosomal Exit Tunnel

et al. 2013

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During protein synthesis the nascent polypeptide chain (NC) extends through the ribosomal exit tunnel (NPET). Also, the large group of macrolide antibiotics binds in the nascent peptide exit tunnel. In some cases interaction of NC with NPET leads to the ribosome stalling, a significant event in regulation of translation. In other cases NC-ribosome interactions lead to pauses in translation that play an important role in cotranslational folding of polypeptides emerging from the ribosome. The precise mechanism of NC recognition in NPET as well as factors that determine NC conformation in the ribosomal tunnel are unknown. A number of derivatives of the macrolide antibiotic 5-O-mycaminosyltylonolide (OMT) containing N-acylated amino acid or peptide residues were synthesized in order to study potential sites of NC-NPET interactions. The target compounds were prepared by conjugation of protected amino acids and peptides with the C23 hydroxyl group of the macrolide. These OMT derivatives showed high although varying abilities to inhibit the firefly luciferase synthesis in vitro. Three glycil-containing derivatives appeared to be strong inhibitors of translation, more potent than parental OMT. Molecular dynamics (MD) simulation of complexes of tylosin, OMT, and some of OMT derivatives with the large ribosomal subunit of E. coli illuminated a plausible reason for the high inhibitory activity of Boc-Gly-OMT. In addition, the MD study detected a new putative site of interaction of the nascent polypeptide chain with the NPET walls.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conjugates of Amino Acids and Peptides with 5-O-Mycaminosyltylonolide and Their Interaction with the Ribosomal Exit Tunnel

et al. 2013

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“…4), thus interfering with peptidyl transferase activity (19,37,38) and resulting in truncated peptides (19). Macrolides with C-5 monosaccharides do not interfere with peptidyl transferase activity but instead block the egress of the nascent peptide from the exit tunnel, leading to peptides up to 8 amino acids long (13,19,27,38,42).…”

Section: Discussionmentioning

confidence: 99%

Induction of Efflux-Mediated Macrolide Resistance in Streptococcus pneumoniae

Chancey

Zhou

Zähner

et al. 2011

Antimicrob Agents Chemother

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The antimicrobial efflux system encoded by the operon mef(E)-mel on the mobile genetic element MEGA in Streptococcus pneumoniae and other Gram-positive bacteria is inducible by macrolide antibiotics and antimicrobial peptides. Induction may affect the clinical response to the use of macrolides. We developed mef(E) reporter constructs and a disk diffusion induction and resistance assay to determine the kinetics and basis of mef(E)-mel induction. Induction occurred rapidly, with a >15-fold increase in transcription within 1 h of exposure to subinhibitory concentrations of erythromycin. A spectrum of environmental conditions, including competence and nonmacrolide antibiotics with distinct cellular targets, did not induce mef(E). Using 16 different structurally defined macrolides, induction was correlated with the amino sugar attached to C-5 of the macrolide lactone ring, not with the size (e.g., 14-, 15-or 16-member) of the ring or with the presence of the neutral sugar cladinose at C-3. Macrolides with a monosaccharide attached to C-5, known to block exit of the nascent peptide from the ribosome after the incorporation of up to eight amino acids, induced mef(E) expression. Macrolides with a C-5 disaccharide, which extends the macrolide into the ribosomal exit tunnel, disrupting peptidyl transferase activity, did not induce it. The induction of mef(E) did not require macrolide efflux, but the affinity of macrolides for the ribosome determined the availability for efflux and pneumococcal susceptibility. The induction of mef(E)-mel expression by inducing macrolides appears to be based on specific interactions of the macrolide C-5 saccharide with the ribosome that alleviate transcriptional attenuation of mef(E)-mel.Macrolides are broad-spectrum antibiotics with complex macrocyclic 14-, 15-, or 16-member lactone rings that bind in the peptide exit tunnel of bacterial ribosomes and inhibit protein synthesis. Macrolides are often recommended as the empirical first-line treatment for upper respiratory bacterial infections, including pneumococcal infections and communityacquired pneumonia. However, bacterial resistance to macrolides is expanding worldwide in Gram-positive bacteria and is now present in almost a third of all invasive Streptococcus pneumoniae isolates (14). The two most common mechanisms of macrolide resistance in bacterial pathogens are modification of the bacterial ribosome, either by methylation or mutation, and extrusion of the drugs from the bacterial cell by an efflux pump. Genes of the erm (erythromycin ribosomal methylases) family of rRNA methylases confer high-level resistance to lincosamides and streptogramins, as well as macrolides (the MLS B phenotype), and can be constitutive or inducible. In the inducible form, resistance develops only after exposure of the bacterium to the macrolide.The best-studied mechanism of inducible MLS B resistance involves the erm(C) gene found in S. aureus and other Grampositive pathogens (4,32,33). Translation of erm(C) is attenuated in the absence of inducers due to...

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