Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721

Slee, Andrew M.; Wuonola, Mark A.; McRipley, Ronald J.; Zajac, Ian; Zawada, M; Bartholomew, P. T.; Gregory, Walter A.; Forbes, Martin

doi:10.1128/aac.31.11.1791

Cited by 205 publications

(143 citation statements)

References 7 publications

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“…They were first discovered in 1978 (E. I. duPont de Nemours & Co.)24 but later abandoned owing to serious toxicity issues 25. Research continued in this area (initiated by Upjohn, later Pharmacia, now Pfizer Inc.), and by 1996, two nontoxic oxazolidinones, linezolid and eperezolid, had been developed ( 1 and 2 ; Figure 3).…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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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.

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Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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“…KaleidaGraph (version 3.5) was from Synergy Software (Reading, PA). The ribotrinucleotide 5Ј-rC-rC-rA-3Ј (CCA) 1 was purchased from Oligos etc. (Wilsonville, OR) and used without purification.…”

Section: Methodsmentioning

confidence: 99%

“…Oxazolidinones, which were first discovered at E. I. DuPont de Nemours and Co. in 1983 (1), are the only new class of synthetic antimicrobial agent introduced into clinical practice within the last 30 years. Although these compounds block protein biosynthesis (2), they inhibit neither translation by polysomes (3) nor the poly(U)-dependent reaction (4).…”

mentioning

confidence: 99%

Oxazolidinones Mechanism of Action: Inhibition of the First Peptide Bond Formation

Patel

Yan

Hobbs

et al. 2001

Journal of Biological Chemistry

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Oxazolidinones are potent inhibitors of bacterial protein biosynthesis. Previous studies have demonstrated that this new class of antimicrobial agent blocks translation by inhibiting initiation complex formation, while post-initiation translation by polysomes and poly(U)-dependent translation is not a target for these compounds. We found that oxazolidinones inhibit translation of natural mRNA templates but have no significant effect on poly(A)-dependent translation. Here we show that various oxazolidinones inhibit ribosomal peptidyltransferase activity in the simple reaction of 70 S ribosomes using initiator-tRNA or N-protected CCA-Phe as a P-site substrate and puromycin as an A-site substrate. Steadystate kinetic analysis shows that oxazolidinones display a competitive inhibition pattern with respect to both the P-site and A-site substrates. This is consistent with a rapid equilibrium, ordered mechanism of the peptidyltransferase reaction, wherein binding of the A-site substrate can occur only after complex formation between peptidyltransferase and the P-site substrate. We propose that oxazolidinones inhibit bacterial protein biosynthesis by interfering with the binding of initiator fMet-tRNA i Met to the ribosomal peptidyltransferase Psite, which is vacant only prior to the formation of the first peptide bond.

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“…[21][22][23] The inescapable linkage between the application of new antibiotics and the development of transferable resistance to those drugs justifies the development of techniques for inventory and characterization of the translational machinery from organisms other than just a few standard laboratory strains. 24 We have used a combination of top-down and bottom-up approaches to characterize the ribosomal proteins of Caulobacter crescentus, a bacterium that is the subject of on-going study in our laboratory.…”

Section: Introductionmentioning

confidence: 99%

A Top-Down/Bottom-Up Study of the Ribosomal Proteins of Caulobacter crescentus

et al. 2006

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Ribosomes from the gram-negative α-proteobacterium Caulobacter crescentus were isolated using standard methods. Proteins were separated using a two-dimensional liquid chromatographic system that allowed the analysis of whole proteins by direct coupling to an ESI-QTOF mass spectrometer and of proteolytic digests by a number of mass spectrometric methods. The masses of 53 of 54 ribosomal proteins were directly measured. Protein identifications and proposed post-translational modifications were supported by proteolysis with trypsin, endoprotease Glu-C and exoproteases carboxypeptidases Y and P. Tryptic peptide mass maps show an average sequence coverage of 62%, and carboxypeptidase C-terminal sequence tagging provided unambiguous identification of the small, highly basic proteins of the large subunit. C. crescentus presents some post-translational modifications that are similar to those of E. coli (e. g. N-terminal acetylation of S9 and S18) along with some unique variations, such as a near absence of L7 and extensive modification of L11. The comprehensive description of this organism's ribosomal proteome provides a foundation for the study of ribosome structure, dependence of post-translational modifications on growth conditions, and the evolution of subcellular organelles.

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Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721

Cited by 205 publications

References 7 publications

Targeting Antibiotic Resistance

Targeting Antibiotic Resistance

Oxazolidinones Mechanism of Action: Inhibition of the First Peptide Bond Formation

A Top-Down/Bottom-Up Study of the Ribosomal Proteins of Caulobacter crescentus

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