The Ketolide Antibiotic ABT-773 Is a Specific Inhibitor of Translation and 50S Ribosomal Subunit Formation in Streptococcus pneumoniae Cells

Champney, W. Scott; Pelt, Jennifer

doi:10.1007/s00284-001-0110-9

Cited by 20 publications

(22 citation statements)

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“…The IC 50 of 7.5 ng/ml found for inhibition of translation and 50S assembly is comparable to the IC 50 s of 5 ng/ml observed for cethromycin (9) and 15 ng/ml measured for telithromycin (10). The solithromycin IC 50 is consistent with MIC 50 values of 15 to 60 ng/ml reported in various studies of S. pneumoniae strains (8,(21)(22)(23)(24)(25).…”

Section: Discussionsupporting

confidence: 77%

“…Methicillin-susceptible Staphylococcus aureus (MSSA) strain RN1786 was obtained from Richard Novick (New York University), and a clinical isolate of methicillin-resistant S. aureus (MRSA) (strain A1024) was provided by Joyce Sutcliffe (Tetraphase Pharmaceuticals) (12). H. influenzae strain CDC G-79 (13) and S. pneumoniae strain ATCC 49619 (9,10) 175 Ci/mmol) were purchased from American Radiochemicals (St. Louis, MO) and MP Biomedical (Solon, OH), respectively. Solithromycin was provided by Cempra Pharmaceuticals (Chapel Hill, NC) and was dissolved at 1 mg/ml in acetic acid at a pH of 5.5.…”

Section: Methodsmentioning

confidence: 99%

“…Its site of binding to the Escherichia coli 50S subunit has been characterized (8). This interaction inhibits protein biosynthesis and should impair bacterial ribosomal subunit formation, much like with other ketolides (9)(10)(11). In this study, the mechanism of action of solithromycin was tested in three important human pathogens, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae.…”

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confidence: 99%

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Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

Rodgers

Frazier

Champney

2013

Antimicrob Agents Chemother

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The continuing increase in antibiotic-resistant microorganisms is driving the search for new antibiotic targets and improved antimicrobial agents. Ketolides are semisynthetic derivatives of macrolide antibiotics, which are effective against certain resistant organisms. Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. This compound binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis. Like other ketolides, it should impair bacterial ribosomal subunit formation. This mechanism of action was examined in strains of Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. The mean 50% inhibitory concentrations (IC 50 s) for solithromycin inhibition of cell viability, protein synthesis, and growth rate were 7.5, 40, and 125 ng/ml for Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The net formation of the 50S subunit was reduced in all three organisms, with IC 50 s similar to those given above. The rates of 50S subunit formation measured by a pulse-chase labeling procedure were reduced by 75% in cells growing at the IC 50 of solithromycin. Turnover of 23S rRNA was stimulated by solithromycin as well. Solithromycin was found to be a particularly effective antimicrobial agent, with IC 50 s comparable to those of telithromycin and significantly better than those of azithromycin and clarithromycin in these three microorganisms.

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Section: Discussionsupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

Rodgers

Frazier

Champney

2013

Antimicrob Agents Chemother

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“…The macrolides form hydrogen bonds with the 23S rRNA at domains II and V and thus inhibit bacterial protein synthesis. Ketolides are known to bypass macrolide resistant mechanisms by improving ribosome binding affinity, especially binding to domain II and evading macrolide efflux mechanisms 60, 61. The structure-activity relationship is paramount in ketolide mechanism of action.…”

Section: Antibacterial Drugsmentioning

confidence: 99%

Newer antibacterial drugs for a new century

Devasahayam¹,

Scheld²,

Hoffman³

2010

Expert Opinion on Investigational Drugs

131

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Antibacterial drug discovery and development has slowed considerably in recent years with novel classes discovered decades ago and regulatory approvals tougher to get. This article describes newer classes of antibacterial drugs introduced or approved after year 2000, their mechanisms of action/ resistance, improved analogs, spectrum of activity and clinical trials. It also discusses new compounds in development with novel mechanisms of action as well as novel unexploited bacterial targets and strategies which may pave the way for combating drug resistance and emerging pathogens in the 21 st century. Keywordsantibacterial; drug discovery; drug resistance Infectious diseases are one of the leading causes of death worldwide, especially in low and middle income (LMIC) countries where second line antibacterial drugs against resistant bacteria are generally unavailable or unaffordable. In upper income countries (UIC), the emergence of multi-drug resistance in both community and hospital acquired infections has outpaced development and delivery of new drugs to the clinic. Most recently, the emergence of carbapenem resistance among Klebsiella sp. and related Gram negative bacteria illustrates the magnitude of the problem, as these multi-drug resistant infections are associated with high mortality rates and few treatment options 1. While the market potential for new antibacterial drugs is estimated in the many billions of dollars 2 , the discovery pipelines of most major pharmaceutical companies run near empty. The paucity of new antibacterial drugs has led the Infectious Disease Society of America (IDSA) and others to call for action in rebuilding infrastructure and efforts to develop next generation drugs.Despite the many grim predictions of failure in combating infectious diseases in the future 3 , 4 , all is not lost, as several classes of new antibacterial compounds as well as derivatives of older therapeutics have emerged. In this review we examine some of these new antibacterial drugs that have recently been approved by the FDA (and EMEA) or are in late stages (phase II development or beyond) of the pipeline. These new drugs belong to the following classes of compounds that include: oxazolidinones, glycopeptides, ketolides, glycylcyclines, carbapenems and fluoroquinolones (Table 1). This article will describe in detail the mechanism of action (novelty), spectrum of activity, selected in vivo efficacy and mechanisms of resistance to these antibacterial drugs and also discusses briefly more new drugs in development (Table 2). We also have included unpublished information reported at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Disease NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptSociety of America (IDSA) 46th Annual Meeting in 2008 and here after noted as ICAAC/ IDSA. In addition, we also explore novel strategies such as targeting host infection response pathways, anti-infective antibodies or the vitamin cofactors of...

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“…It has been suggested that the inhibition of 50S assembly is lethal for bacteria because of RNase degradation of the ribosomal RNAs (27,30,(32)(33)(34), but no causal link has been established, and inhibitors of 50S assembly that are merely bacteriostatic also cause the degradation of rRNA (155).…”

Section: Rrna Degradation and Lethalitymentioning

confidence: 99%

Inhibition of Bacterial Ribosome Assembly: a Suitable Drug Target?

Maguire

2009

Microbiol Mol Biol Rev

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SUMMARY The assembly of bacterial ribosomes is viewed with increasing interest as a potential target for new antibiotics. The in vivo synthesis and assembly of ribosomes are briefly reviewed here, highlighting the many ways in which assembly can be perturbed. The process is compared with the model in vitro process from which much of our knowledge is derived. The coordinate synthesis of the ribosomal components is essential for their ordered and efficient assembly; antibiotics interfere with this coordination and therefore affect assembly. It has also been claimed that the binding of antibiotics to nascent ribosomes prevents their assembly. These two contrasting models of antibiotic action are compared and evaluated. Finally, the suitability and tractability of assembly as a drug target are assessed.

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The Ketolide Antibiotic ABT-773 Is a Specific Inhibitor of Translation and 50S Ribosomal Subunit Formation in Streptococcus pneumoniae Cells

Cited by 20 publications

References 33 publications

Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

Newer antibacterial drugs for a new century

Inhibition of Bacterial Ribosome Assembly: a Suitable Drug Target?

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