Macrolide Resistance Conferred by Base Substitutions in 23S rRNA

Vester, Birte; Douthwaite, Stephen

doi:10.1128/aac.45.1.1-12.2001

Cited by 500 publications

(487 citation statements)

References 156 publications

Supporting

Mentioning

454

Contrasting

Unclassified

Order By: Relevance

“…The presence of a hydrophilic molecule, like spermine or spermidine, in the heart of this hydrophobic region could destabilize macrolide binding. Indeed, organisms like H. marismortui, which orient a hydrophilic group (the exocyclic N2 of G2099) into the center of this region, are more resistant to macrolides than those having adenosine at this position (40). More probably, polyamines may affect the stability of the covalent bond formed between the ethylaldehyde substituent at the C6 position of the lactone ring and the N6 of A2062 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Polyamines Affect Diversely the Antibiotic Potency

Πετρόπουλος

Xaplanteri

Dinos

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The effects of spermine on peptidyltransferase inhibition by an aminohexosylcytosine nucleoside, blasticidin S, and by a macrolide, spiramycin, were investigated in a model system derived from Escherichia coli, in which a peptide bond is formed between puromycin and AcPhe-tRNA bound at the P-site of poly(U)-programmed ribosomes. Kinetics revealed that blasticidin S, after a transient phase of interference with the A-site, is slowly accommodated near to the P-site so that peptide bond is still formed but with a lower catalytic rate constant. At high concentrations of blasticidin S (>10 ؋ K i ), a second drug molecule binds to a weaker binding site on ribosomes, and this may account for the onset of a subsequent mixed-noncompetitive inhibition phase. Spermine enhances the blasticidin S inhibitory effect by facilitating the drug accommodation to both sites. On the other hand, spiramycin (A) was found competing with puromycin for the A-site of AcPhe-tRNA⅐poly(U)⅐70 S ribosomal complex (C) via a two-step mechanism, according to which the fast formation of the encounter complex CA is followed by a slow isomerization to a tighter complex, termed C*A. In contrast to that observed with blasticidin S, spermine reduced spiramycin potency by decreasing the formation and stability of complex C*A. Polyamine effects on drug binding were more pronounced when a mixture of spermine and spermidine was used, instead of spermine alone. Our kinetic results correlate well with cross-linking and crystallographic data and suggest that polyamines bound at the vicinity of the antibiotic binding pockets modulate diversely the interaction of these drugs with ribosomes.Blasticidin S and spiramycin are representatives of two distinct antibiotic families, the aminohexosylcytosine nucleosides and the 16-membered lactone ring macrolides, respectively, both of which have been proposed to inhibit protein synthesis by binding to the large ribosomal subunit. Blasticidin S consists of a cytosine bonded to a pyranose ring, to which an amino acid-like substituent is attached (see Fig. 1). Therefore, it is not surprising that blasticidin S and puromycin have been considered as iso-structural, both with one another and with the 3Ј-end of aminoacyl-tRNA (1, 2). Consistently, blasticidin S has been found to inhibit the binding of CACCA (Phe) to the A-site of ribosomes (3) and to compete with designated A-site inhibitors (4). In addition, the inhibition of peptidyl-or AcPhe 1 -puromycin synthesis by this antibiotic shows a competitive phase in concert with noncompetitive or mixed-noncompetitive phases (5, 6), a fact supporting the notion that blasticidin S influences, at least transiently, the affinity of the A-site. Further support derives from chemical probing studies in Escherichia coli ribosomes (7), suggesting that blasticidin S protects A2439, one of the three nucleosides in domain V of 23 S rRNA, which show altered chemical reactivity on removal of the aminoacyl group from A-site-bound tRNAs (8). Moreover, A2439 is one of the preferable cross-linking...

show abstract

Section: Discussionmentioning

confidence: 99%

Polyamines Affect Diversely the Antibiotic Potency

Πετρόπουλος

Xaplanteri

Dinos

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This takes place, unsurprisingly, on A2058Ec, the key component of the binding pocket. Mono and dimethylation of A2058Ec are carried out by erythromycin ribosome methylation (Erm) methyltransferases 60. While monomethylation confers only moderate resistance to macrolides and none to ketolides, dimethylation leads to complete blocking of the binding site and high resistance to both macrolides and ketolides 18, 61.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

View full text Add to dashboard Cite

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

show abstract

“…This mechanism of resistance is therefore of special relevance in microorganisms with only one or two rrn loci (Leclercq, 2002;Vester & Douthwaite, 2001) also being described in microorganisms with three or four rrn loci (Chisholm et al, 2010;Saito et al, 2012). Enterobacteriaceae such as E. coli, Salmonella spp.…”

Section: S Rrna Base Substitutionsmentioning

confidence: 99%