Evernimicin (SCH27899) Inhibits a Novel Ribosome Target Site: Analysis of 23S Ribosomal DNA Mutants

Adrian, Peter V.; Mendrick, Cara; Loebenberg, David; McNicholas, Paul M.; Shaw, Karen Joy; Klugman, Keith P.; Hare, R S; Black, Todd A.

doi:10.1128/aac.44.11.3101-3106.2000

Cited by 46 publications

(38 citation statements)

References 25 publications

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“…A vacina pneumocócica heptavalente é altamente eficaz na prevenção de doença invasiva em crianças 115 . A imunização de crianças com as novas vacinas conjugadas para Haemophilus influenza tipo b e pneumococos nos países em desenvolvimento poderá ter impacto, a exemplo do que ocorreu nos países desenvolvidos, em reduzir consideravelmente a morbidade e a mortalidade por pneumonias agudas, a taxa de hospitalização e os custos em saúde pública nesses países 103 .…”

Section: Conclusõesunclassified

Diagnóstico etiológico das pneumonias: uma visão crítica

Rodrigues

Filho

Bush

2002

J. Pediatr. (Rio J.)

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Objetivo: revisar a literatura quanto ao diagnóstico etiológico das pneumonias agudas na faixa etária pediátrica. Fonte dos dados: revisão sistemática das citações do Medline e do Lilacs.Síntese dos dados: a utilização dos novos métodos diagnósticos, particularmente as técnicas imunológicas e a reação em cadeia da polimerase, de uso ainda incipiente no Brasil, tem se mostrado importante para a investigação epidemiológica e para a melhora no diagnóstico específico em termos de sensibilidade, especificidade e rapidez de resultados, com finalidade de orientação terapêutica adequada. A revisão dos estudos epidemiológicos das pneumonias agudas adquiridas na comunidade mostrou que o Streptococcus pneumoniae continua sendo o agente bacteriano mais importante, em todas as faixas etárias, tanto nos países desenvolvidos quanto nos em desenvolvimento. A resistência desse agente à penicilina e às cefalosporinas tem aumentado progressivamente em todos os continentes e tem-se constituído em um fator de preocupação. Os agentes de pneumonias atípicas, Mycoplasma pneumoniae e Chlamydia pneumoniae mostram-se, atualmente, como agentes importantes de pneumonias agudas adquiridas na comunidade, particularmente em crianças acima de 4 a 5 anos de idade, correspondendo, em países desenvolvidos, a cerca de até um terço dos casos. No entanto, ainda não está definida a sua importância epidemiológica nos países em desenvolvimento. O vírus respiratório sincicial é um agente freqüente de pneumonias agudas adquiridas na comunidade, pode determinar quadros mais graves, particularmente nos lactentes e crianças menores, sendo muito importante a sua investigação em crianças hospitalizadas por doença do trato respiratório inferior. A utilização das novas vacinas conjugadas contra Streptococcus pneumoniae e Haemophilus influenzae tipo b tiveram um impacto importante na morbidade e mortalidade das infecções causadas por esse agentes.Conclusões: a monitorização microbiológica e antimicrobiana deve ser um trabalho dinâmico e contínuo, e a procura e o desenvolvimento de novas vacinas, particularmente contra o VRS, poderá causar um grande impacto na prevenção das pneumonias agudas na infância.J Pediatr (Rio J) 2002; 78 (Supl.2): S129-S140: pneumonia, pneumopatias, diagnóstico. AbstractObjectives: to search literature related to the etiological diagnosis of acute pneumonia in children. Sources: systematic review of Medline and Lilacs databases.Summary of the findings: the use of new diagnostic methods such as immunological techniques and polymerase chain reaction has proven invaluable for specific diagnosis and epidemiological investigation, showing adequate sensitivity, specificity and promptness of results, with the aim of guiding therapy properly. Review of epidemiological studies of community acquired pneumonia showed that Streptococcus pneumoniae is still one of the most significant etiologic agents in all age groups, in developing and industrialized countries. Resistance of this agent to penicillin and cephalosporins is increasing in all continents...

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Section: Conclusõesunclassified

Diagnóstico etiológico das pneumonias: uma visão crítica

Rodrigues

Filho

Bush

2002

J. Pediatr. (Rio J.)

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“…However, given the enormous size and functional complexity of the ribosome, the number of possible antibiotic targets and sites of functional importance is likely to exceed those currently known. The occasional serendipitous discovery of antibiotics acting on novel ribosomal sites and subsequent recognition of the functional significance of such sites support this notion (8,9). Nonetheless, only a few attempts have been made to identify new sites of antibiotic action and to understand the activity of the associated centers in the ribosome (10).…”

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Deleterious mutations in small subunit ribosomal RNA identify functional sites and potential targets for antibiotics

Yassin

Fredrick

Mankin

2005

Proc. Natl. Acad. Sci. U.S.A.

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Many clinically useful antibiotics interfere with protein synthesis in bacterial pathogens by inhibiting ribosome function. The sites of action of known drugs are limited in number, are composed primarily of ribosomal RNA (rRNA), and coincide with functionally critical centers of the ribosome. Nucleotide alterations within such sites are often deleterious. To identify functional sites and potential sites of antibiotic action in the ribosome, we prepared a random mutant library of rRNA genes and selected dominant mutations in 16S rRNA that interfere with cell growth. Fifty-three 16S rRNA positions were identified whose mutation inhibits protein synthesis. Mutations were ranked according to the severity of the phenotype, and the detrimental effect of several mutations on translation was verified in a specialized ribosome system. Analysis of the polysome profiles of mutants suggests that the majority of the mutations directly interfered with ribosome function, whereas a smaller fraction of mutations affected assembly of the small ribosomal subunit. Twelve of the identified mutations mapped to sites targeted by known antibiotics, confirming that deleterious mutations can be used to identify antibiotic targets. About half of the mutations coincided with known functional sites in the ribosome, whereas the rest of the mutations affected ribosomal sites with less clear functional significance. Four clusters of deleterious mutations in otherwise unremarkable ribosomal sites were identified, suggesting their functional importance and potential as antibiotic targets.16S rRNA ͉ 30S subunit ͉ resistance ͉ ribosome ͉ translation W ith a molecular mass of Ϸ2.5 million Da and Ͼ50 different RNA and protein building blocks, the ribosome represents one of the largest and most complex enzymes in the cell. Ribosomal RNA (rRNA) accounts for two-thirds of the ribosome and is responsible for its main functions in protein synthesis: interpretation of genetic information and polymerization of amino acids into a polypeptide. rRNA is also intimately involved in known auxiliary activities of the ribosome, such as nascent peptide release, binding of translation factors, GTP hydrolysis, etc. (reviewed in ref. 1).The ribosome is the predominant antibiotic target in the bacterial cell. A large variety of natural and synthetic antibiotics interfere with translation by binding to rRNA and preventing the correct placement of ribosomal ligands, corrupting rRNA structure, or affecting conformational flexibility of rRNA (2). Advantages of the ribosome as an antibiotic target may stem from its RNA-based design. The multiplicity of rRNA genes in microbial genomes makes it difficult for a microorganism to develop resistance by mutating the drug-binding site (3). Furthermore, RNA offers fewer mutational options than protein enzymes (3 versus 19, respectively), which makes it more difficult for a microbial pathogen to ''find'' a mutation that would reduce antibiotic binding without compromising functional integrity of the enzyme. In the clinical setting, ...

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“…EVN and AVI display excellent antimicrobial activity against Gram-positive bacteria (3), including methicillin-resistant Staphylococcus aureus (7), as well as some Gram-negative bacteria, such as Borrelia burgdorferi (8). Importantly, strains resistant to EVN and AVI do not display cross-resistance to any other known antimicrobial agents, including ribosome-targeting antibiotics, such as chloramphenicol, tetracycline, or erythromycin (9,10).…”

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Structures of the orthosomycin antibiotics avilamycin and evernimicin in complex with the bacterial 70S ribosome

Arenz¹,

Juette

Graf³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The ribosome is one of the major targets for therapeutic antibiotics; however, the rise in multidrug resistance is a growing threat to the utility of our current arsenal. The orthosomycin antibiotics evernimicin (EVN) and avilamycin (AVI) target the ribosome and do not display cross-resistance with any other classes of antibiotics, suggesting that they bind to a unique site on the ribosome and may therefore represent an avenue for development of new antimicrobial agents. Here we present cryo-EM structures of EVN and AVI in complex with the Escherichia coli ribosome at 3.6- to 3.9-Å resolution. The structures reveal that EVN and AVI bind to a single site on the large subunit that is distinct from other known antibiotic binding sites on the ribosome. Both antibiotics adopt an extended conformation spanning the minor grooves of helices 89 and 91 of the 23S rRNA and interacting with arginine residues of ribosomal protein L16. This binding site overlaps with the elbow region of A-site bound tRNA. Consistent with this finding, single-molecule FRET (smFRET) experiments show that both antibiotics interfere with late steps in the accommodation process, wherein aminoacyl-tRNA enters the peptidyltransferase center of the large ribosomal subunit. These data provide a structural and mechanistic rationale for how these antibiotics inhibit the elongation phase of protein synthesis.

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Evernimicin (SCH27899) Inhibits a Novel Ribosome Target Site: Analysis of 23S Ribosomal DNA Mutants

Cited by 46 publications

References 25 publications

Diagnóstico etiológico das pneumonias: uma visão crítica

Diagnóstico etiológico das pneumonias: uma visão crítica

Deleterious mutations in small subunit ribosomal RNA identify functional sites and potential targets for antibiotics

Structures of the orthosomycin antibiotics avilamycin and evernimicin in complex with the bacterial 70S ribosome

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