Macrolide antibiotics inhibit 50S ribosomal subunit assembly in Bacillus subtilis and Staphylococcus aureus

Champney, W. Scott; Burdine, R

doi:10.1128/aac.39.9.2141

Cited by 60 publications

(43 citation statements)

References 23 publications

(16 reference statements)

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“…Significantly, this work is the first to describe a nonmacrolide antibiotic which functions by inhibition of 50S ribosomal subunit formation in cells (3,9). Evernimicin specifically prevents the complete formation of the large ribosomal subunit, apparently inhibiting both translation and assembly by 50S particle binding.…”

Section: Discussionmentioning

confidence: 99%

“…The macrolide antibiotics specifically prevent the formation of the 50S subunit and do not stimulate the breakdown of mature 50S particles (3,9). Evernimicin was tested for a stimulatory effect on 50S subunit breakdown.…”

Section: Resultsmentioning

confidence: 99%

“…E-112, p. 202, 1998), including methicillin-resistant Staphylococcus aureus (MRSA) strains (19). It is also very effective against Legionella species (11 We have identified a novel target for macrolide antibiotics in bacterial cells, the assembly of 50S ribosomal subunits (3)(4)(5). Macrolide and ketolide antibiotics have equivalent inhibitory effects on both translation and 50S subunit formation in S. aureus (7,8).…”

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confidence: 99%

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Evernimicin (SCH27899) Inhibits both Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

Champney

Tober

2000

Antimicrob Agents Chemother

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The effects of the everninomicin antibiotic evernimicin (SCH27899) on growing Staphylococcus aureus cells were investigated. Cellular growth rates and viable cell numbers decreased with increasing antibiotic concentrations. The rate of protein synthesis, measured as 35 S-amino acid incorporation, declined in parallel with the growth rate. Significantly, the formation of the 50S ribosomal subunit was inhibited in a dose-dependent fashion as well. 30S ribosomal subunit synthesis was not affected over the same concentration range. Evernimicin did not stimulate the breakdown of mature ribosomal subunits. Pulse-chase labeling experiments revealed a reduced rate of 50S subunit formation in drug-treated cells. Two erythromycin-resistant strains of S. aureus that carried the ermC gene were as sensitive as wild-type cells to antibiotic inhibition. In addition, two methicillin-resistant S. aureus organisms, one sensitive to erythromycin and one resistant to the macrolide, showed similar sensitivities to evernimicin. These results suggest a use for this novel antimicrobial agent against antibiotic-resistant bacterial infections.In the struggle to keep up with the current increase in the number of antibiotic-resistant infectious organisms, both new antimicrobial agents and new cellular targets must be found (10). A compound identified 35 years ago has recently been reinvestigated as a new and potentially effective antibiotic. The everninomicins are a group of complex, sugar-derived antibiotics isolated from Micromonospora carbonacea (25, 26). They were described and characterized many years ago, but very few studies have been conducted to examine their modes of action (12, 21; A. K. Ganguly and A. K. Saksena, Communications to the editor, J. Antibiot. (Tokyo) 28:707-709, 1975). Avilamycin, a polysaccharide antibiotic with similarities to the everninomicins, was shown to affect protein synthesis by interacting with the 30S ribosomal subunit (27). This compound has been used as an antimicrobial agent in animal feed (1).Recently, another everninomicin, evernimicin (SCH 27899), has been examined in more detail (13,14,24 We have identified a novel target for macrolide antibiotics in bacterial cells, the assembly of 50S ribosomal subunits (3-5). Macrolide and ketolide antibiotics have equivalent inhibitory effects on both translation and 50S subunit formation in S. aureus (7,8). Since it has been suggested that evernimicin inhibits protein synthesis by interacting with the 50S subunit (Adrian and Klugman, 38th ICAAC), we decided to investigate its inhibitory effects on translation and subunit assembly in a systematic fashion. We found that both translation and 50S subunit formation were targets for inhibition in wild-type S. aureus cells and in both MRSA and erythromycin-resistant mutant strains. The significance of these findings are discussed in terms of the effects both on 50S subunit formation and on the potential clinical use of this antimicrobial agent. MATERIALS AND METHODSMeasurements of cell growth, subunit assembly, and...

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Evernimicin (SCH27899) Inhibits both Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

Champney

Tober

2000

Antimicrob Agents Chemother

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“…They block the exit tunnel through which newly synthesised peptides move away from the peptidyl transferase centre, obstructing elongation of the peptide chain. It is thought that a second inhibitory activity blocks the assembly of rRNAs and r-proteins resulting in inhibition of formation of the large 50S ribosomal subunit [24,25]. It is not clear whether these mechanisms of action are the same for slowly growing mycobacteria as for M. smegmatis.…”

Section: Mechanism Of Actionmentioning

confidence: 95%

Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

et al. 2015

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Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen. @ERSpublications Macrolides deserve more research interest for use against MDR-TB as results appear to be more promising than thought http://ow.ly/LDFjp

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“…Cells were collected by centrifugation at 6,500 rpm for 10 min and held at Ϫ70°C until lysis. The cells were lysed with a lysozyme freeze-thaw method as described previously (7). The lysates were spun on 5 to 20% sucrose gradients in S buffer (10 mM Tris-HCl, pH 8.0, 0.5 mM Mg acetate, 50 mM NH 4 Cl) to separate ribosome particles.…”

Section: Methodsmentioning

confidence: 99%

Hygromycin B Inhibition of Protein Synthesis and Ribosome Biogenesis in Escherichia coli

McGaha

Champney

2007

Antimicrob Agents Chemother

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The aminoglycoside antibiotic hygromycin B was examined in Escherichia coli cells for inhibitory effects on translation and ribosomal-subunit formation. Pulse-chase labeling experiments were performed, which verified lower rates of ribosomal-subunit synthesis in drug-treated cells. Hygromycin B exhibited a concentrationdependent inhibitory effect on viable-cell numbers, growth rate, protein synthesis, and 30S and 50S subunit formation. Unlike other aminoglycosides, hygromycin B was a more effective inhibitor of translation than of ribosomal-subunit formation in E. coli. Examination of total RNA from treated cells showed an increase in RNA corresponding to a precursor to the 16S rRNA, while mature 16S rRNA decreased. Northern hybridization to rRNA in cells treated with hygromycin B showed that RNase II-and RNase III-deficient strains of E. coli accumulated 16S rRNA fragments upon treatment with the drug. The results indicate that hygromycin B targets protein synthesis and 30S ribosomal-subunit assembly.Currently, only a limited number of antibiotics are available to treat multidrug-resistant strains of infectious bacteria, and resistance to even the newest antimicrobial agents is appearing (13). Increasing antibiotic resistance in microbial populations has necessitated the search for alternate cellular targets for new and existing antimicrobial agents. There are many antibiotics available that inhibit translation in bacterial cells by binding to the 30S or 50S ribosomal subunit (3). It has been observed that a number of ribosomal antibiotics possess a second inhibitory activity that prevents ribosomal-subunit assembly. The formation of a functional ribosome is a vital cellular process and is therefore also an important cellular target (4).In order to broaden our understanding of subunit assembly inhibitors, it is important to examine new or poorly studied antibiotics for their possible effects on inhibition of subunit formation. Identifying and comparing these antimicrobial agents will aid in the search for more suitable targets for future antibiotics. Crystallographic data have been obtained for several antibiotics from the aminoglycoside class (2, 25). These studies have shown that binding occurs through unique base interactions in the decoding center of the 30S ribosome, which effectively halts translation by preventing movements necessary for protein synthesis to occur (8). Recent work with the aminoglycoside compounds neomycin and paromomycin has shown that these antimicrobial agents have a second inhibitory target, which is inhibition of 30S ribosomal-subunit formation (18,19). These drugs are capable of inhibiting 30S ribosomalsubunit formation by stalling assembly at an intermediate phase of 30S biosynthesis.There are many antibiotics that target translation by binding to ribosomal subunits that have not been examined for possible inhibitory effects on ribosomal-subunit assembly. One of those antimicrobial agents is the aminoglycoside hygromycin B, a 30S subunit translational inhibitor. Most aminoglycosid...

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Macrolide antibiotics inhibit 50S ribosomal subunit assembly in Bacillus subtilis and Staphylococcus aureus

Cited by 60 publications

References 23 publications

Evernimicin (SCH27899) Inhibits both Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

Evernimicin (SCH27899) Inhibits both Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

Hygromycin B Inhibition of Protein Synthesis and Ribosome Biogenesis in Escherichia coli

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