DOCSLIB.ORG

Ribosome Assembly As Antimicrobial Target

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ribosome Assembly As Antimicrobial Target antibiotics Article Ribosome Assembly as Antimicrobial Target Rainer Nikolay 1,*,†, Sabine Schmidt 2,†, Renate Schlömer 2, Elke Deuerling 2,* and Knud H. Nierhaus 1 1 Institut für Medizinische Physik und Biophysik, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] 2 Molecular Microbiology, University of Konstanz, Konstanz 78457, Germany; [email protected] (S.S.); [email protected] (R.S.) * Correspondence: [email protected] (R.N.); [email protected] (E.D.); Tel.: +49-30-450-524165 (R.N.); +49-7531-88-2647 (E.D.) † These authors contributed equally to this work. Academic Editor: Claudio O. Gualerzi Received: 31 March 2016; Accepted: 16 May 2016; Published: 27 May 2016 Abstract: Many antibiotics target the ribosome and interfere with its translation cycle. Since translation is the source of all cellular proteins including ribosomal proteins, protein synthesis and ribosome assembly are interdependent. As a consequence, the activity of translation inhibitors might indirectly cause defective ribosome assembly. Due to the difficulty in distinguishing between direct and indirect effects, and because assembly is probably a target in its own right, concepts are needed to identify small molecules that directly inhibit ribosome assembly. Here, we summarize the basic facts of ribosome targeting antibiotics. Furthermore, we present an in vivo screening strategy that focuses on ribosome assembly by a direct fluorescence based read-out that aims to identify and characterize small molecules acting as primary assembly inhibitors. Keywords: protein synthesis as preferential target of antibiotics; ribosome as antibiotic target; inhibitors of ribosome assembly; concepts for identifying assembly inhibitors 1. Introduction Most antibiotics are microbial secondary metabolites mainly produced by actinomycetes. The production is usually induced by unfavorable growth conditions, when the producer has turned into the stationary or sporulation phase and its own metabolic activity is sharply reduced. Under these conditions, antibiotics will block the growth of better adapted competitors and thus prevent a further impairment of life conditions (for review, see [1]). Antibiotics therefore improve the survival chance of the producer, which represents the selective force for the natural development of antibiotics. Under these restricted conditions, synthesis of nucleic acids and protein synthesis is strongly reduced in the producer cell, which explains that, in many cases, the producer is not resistant against its own product. Antibiotics are chemically extremely diverse. The synthesis by microorganisms and a molecular weight less than 1000 Da are the only common features [2]. Nowadays, the term antimicrobials (short for antimicrobial substances) is used, which includes both natural products (antibiotics) and semi-synthetic or full-synthetic substances (chemotherapeutics). In addition to the wide chemical spectrum, the target spectrum is also enormous: More than 160 cellular targets have been described [3]. Examples are replication (e.g., nalidixic acid), transcription (e.g., rifamycin), translation (e.g., chloramphenicol) and the synthesis of the cell wall (e.g., penicillin). Most of the antibiotics inhibit the translating ribosome because, due to its complicated structure, it offers many interference points. The Escherichia coli ribosome contains 57 different components, 54 proteins and three ribosomal RNAs [4], and all of them are present in one copy per ribosome except the protein bL12, which is Antibiotics 2016, 5, 18; doi:10.3390/antibiotics5020018 www.mdpi.com/journal/antibiotics Antibiotics 2016, 5, 18 2 of 13 presentAntibiotics in four 2016 copies., 5, 18 Nevertheless, the binding sites of the antibiotics are concentrated at and2 of around 13 functional hot spots of the small 30S and the large 50S subunit of the bacterial ribosome (Figure1a,b). copies. Nevertheless, the binding sites of the antibiotics are concentrated at and around functional These sites are often dominated or exclusively built by elements of the rRNA (ribosomal RNA), and, hot spots of the small 30S and the large 50S subunit of the bacterial ribosome (Figure 1a,b). These sites importantly,are often dominated the multiplicity or exclusively of rrn operons built by presentelements in of most the rRNA bacterial (ribosomal species RNA), aggravates and, importantly, development of resistancethe multiplicity [5]. Mutations of rrn operons in onlypresent one in genemost bacterial have low specie impacts aggravates and multiple development mutations of resistance are of low probability[5]. Mutations [6]. in only one gene have low impact and multiple mutations are of low probability [6]. FigureFigure 1. Antibiotic1. Antibiotic target target sites sites of of bacterial bacterial ribosomes.ribosomes. (a (a) )a afew few antibiotic antibiotic target target sites sites on onthe the30S 30S subunitsubunit mentioned mentioned in thein the text. text. Tet, Tet, tetracycline; tetracycline; Neo,Neo, neomycin, Str, Str, streptomycin; streptomycin; (b) ( bsome) some antibiotic antibiotic target sites on the 50S subunit. Cam, chloramphenicol; Lin, lincomycin. (from [7], modified, courtesy target sites on the 50S subunit. Cam, chloramphenicol; Lin, lincomycin. (from [7], modified, courtesy of Daniel N. Wilson, Munich Gene Center). of Daniel N. Wilson, Munich Gene Center). Most of the natural antibiotics inhibit the peptidyltransferase center (PTC) on the 50S subunit (FigureMost of 1a; the [8-10]). natural Reasons antibiotics for the inhibitprevalence the of peptidyltransferase the PTC as antibiotic center target (PTC)are (i) the on high the 50S number subunit (Figureof crevices1a; [ 8–10 allowing]). Reasons binding for theof small prevalence molecules of the with PTC high as affinity; antibiotic (ii) targetthe fact are that (i) the PTC high needs number a of creviceshigh allowingamount of binding structural of small flexibility molecules and any with interference high affinity; by drug (ii) the binding fact that or mutations the PTC needs causing a high amountresistance of structural might hamper flexibility the andspeed any and/or interference accuracy byof translation, drug binding which ormutations leads to the causing final outcome resistance mightthat hamper any rescuing the speed mutations and/or within accuracy the PTC of are translation, associated whichwith high leads fitness to the costs final [10]. outcome that any The most common target site of the 30S subunit is the decoding center of the A site, where the rescuing mutations within the PTC are associated with high fitness costs [10]. large group of aminoglycosides interferes with the fidelity of aminoacyl-tRNA(aa-tRNA)·EF-Tu·GTP The most common target site of the 30S subunit is the decoding center of the A site, where the selection (Figure 1b). Examples of binding sites on the 30S part of the A site outside the decoding center large group of aminoglycosides interferes with the fidelity of aminoacyl-tRNA(aa-tRNA)¨ EF-Tu¨ GTP are the tetracyclines, which block stable binding of aa-tRNAs to the A site. The sketch of the ribosomal selectionfunctions (Figure in Figure1b). Examples 2 summarizes of binding the interference sites on points the 30S of partthe various of the Agroups site outside of antibiotics the decoding with centerribosomal are the functions. tetracyclines, Some antibiotics which block act directly stable on binding translational of aa-tRNAs G-proteins. to theOne Aexample site. The is kirromycin, sketch of the ribosomalwhich functionsbinds to the in elongation Figure2 summarizes factor EF-Tu·GTP the interference and blocks points its switch of the into various the GDP groups conformer of antibiotics after withdelivery ribosomal of the functions. aa-tRNA Someto the antibioticsA site. The result act directly is that onEF-Tu translational remains on G-proteins. the ribosome One and examplethus is kirromycin,blocks protein which synthesis. binds Another to the elongation example is fusidic factor acid EF-Tu (FA)¨ GTP acting and on blocks the second its switch elongation into factor the GDP conformerG (EF-G). after EF-G delivery is responsible of the aa-tRNA for the translocation to the A site. of Theribosomes result isto thatthe next EF-Tu codon remains of the on mRNA the ribosome after anda thus decoding blocks step. protein FA also synthesis. blocks the Another conformational example isswitch fusidic into acid the (FA)GDP actingconformer on the of secondEF-G, which elongation is factornecessary G (EF-G). for EF-Gthe dissociation is responsible of this for factor the translocation after it has fulfilled of ribosomes its ribosomal to the function. next codon of the mRNA after a decoding step. FA also blocks the conformational switch into the GDP conformer of EF-G, which is necessary for the dissociation of this factor after it has fulfilled its ribosomal function. Antibiotics 2016, 5, 18 3 of 13 Antibiotics 2016, 5, 18 3 of 13 Kir, Str Tet Ksg Ede Cam Pmn 70S-scanning 50S initiation Ery, Tel FA FA Neo HygB Cam Ths Pmn Vio Figure 2. Overview of some antibiotics interfering with ribosomal functions. Kir, kirromycin; Str, Figure 2. Overview of some antibiotics interfering with ribosomal functions. Kir, kirromycin; Str, streptomycin, tet, tetracycline; Cam, chloramphenicol; Pmn, puromycin; FA, fusidic acid; Neo, streptomycin, tet, tetracycline; Cam, chloramphenicol; Pmn, puromycin; FA, fusidic acid; Neo, neomycin, HygB, hygromycin B; Ths, thiostrepton; Vio, viomycin;
Load more

Recommended publications
  • CLINICAL USE of RIFABUTIN, a RIFAMYCIN-CLASS ANTIBIOTIC, for the TREATMENT of TUBERCULOSIS (A Supplement to the 2008 Revision Of“ Standards for Tuberculosis Care”)
    Kekkaku Vol. 86, No. 1: 43, 2011 43 CLINICAL USE OF RIFABUTIN, A RIFAMYCIN-CLASS ANTIBIOTIC, FOR THE TREATMENT OF TUBERCULOSIS (A supplement to the 2008 revision of“ Standards for tuberculosis care”) August, 2008 The Treatment Committee of the Japanese Society for Tuberculosis The Treatment Committee of the Japanese Society for [Dosage and administration of rifabutin] Tuberculosis published statements on the“ Standards for Rifabutin, 5 mg/kg in body weight/day, maximum 300 mg/ tuberculosis care” in April 2008. Therein we referred to day, once daily. rifampicin as follows“; Use of rifampicin requires attention The dosage of rifabutin can be increased up to the maximum because of the interactions with a number of other drugs. daily dose of 450 mg in cases where decreased rifabutin serum Particularly for HIV-infected patients who need antiviral levels are expected due to anti-HIV drugs such as efavirenz, drugs, the replacement of rifampicin by rifabutin should be and in other cases if necessary. considered”. Rifabutin, belonging to rifamycin-class antibiotics In non-HIV-infected patients, rifabutin can be used for like rifampicin, causes less significant drug-drug interactions intermittent treatment with a regimen of twice or three times a than rifampicin, and can be used in combination with antiviral week, with the same dosage as daily administration. drugs mentioned above. In July 2008, rifabutin was approved as antituberculous drug, and is expected to be added to the drug [Important points for use of rifabutin] price listing in the near future*. Therefore, to the published (1) Rifabutin causes drug interactions due to induction of opinions, we add new statements concerning the use of rifabutin hepatic enzyme though less significantly than rifampicin.
    [Show full text]
  • RIFAMPICIN Productinformation Sigma Prod
    RIFAMPICIN ProductInformation Sigma Prod. No. R3501 CH3 CH3 CAS NUMBER: 13292-46-1 HO SYNONYMS: Tubocin; Sinerdol; Rimactan; L-5103; Dione-21 Acetate; Archidyn; Arficin; 3-(4- CH3 O O OH O Methylpiperazinyliminomethyl)-rifamycin SV; NSC 113926; C OH OH CH 1 2 3 H C Rifampin ; Rifaldazine; Rifamycin AMP H3C 3 O NH H3C PHYSICAL PROPERTIES: CH3 N CH N Appearance: Orange-brown to red-brown powder.3 O OH N Molecular formula: C43H58N4O12 O Molecular weight: 823.0 O CH3 CH3 EmM (max absorbance, phosphate buffer, pH 7.38): 33.20 (237 nm); 32.10 (255 nm); 27.00 (334 nm); 15.40 (475 nm)2,4 pKa (in water):1.7 (4-hydroxyl group), 7.9 (4-piperazine nitrogen); in methylcellosolve-water (4:1): 3.6 (4- hydroxyl group), 6.7 (3-piperazine nitrogen)4 pI (in water): 4.84 25° 4 Optical rotation: [α]D =+10.6° (c=0.5% in CDCl3) Melting point: 183-188°C (dec.)2,4 METHOD OF PREPARATION: Methods of preparation have been reported.4,5 The NMR, UV, IR, Mass spectra, Thin-Layer chromatography and HPLC methods of detection have been reported.4,5,6 A colorimetric test for identification was reported.4 STABILITY / STORAGE: Rifampicin (Rif) should be stable for at least two years when stored desiccated at -20°C and protected from light.3 Rif is stable as a solid at temperatures up to 70EC.4 SOLUBILITY / SOLUTION STABILITY: Rif is soluble in dimethylsulfoxide (~100mg/mL), dimethylformamide, methanol (16 mg/ml, 25EC), chloroform (349 mg/ml, 25°C), ethyl acetate (108 mg/ml, 25°C), and acetone (14 mg/ml, 25°C).4,6,7,8,9 Rif is slightly soluble in water at 25°C: 2.5 mg/ml, pH 7.3; 1.3 mg/ml, pH 4.3; and in 95% ethanol (∼10 mg/mL).4 Rif is soluble at 37°C: in 0.1 N HCl, 200 mg/ml and in phosphate buffer pH 7.4, 9.9 mg/ml.4 R3501 Page 1 of 4 03/28/97 - ARO RIFAMPICIN Sigma Prod.
    [Show full text]
  • Antimicrobials: Leaky Barrier Boosts Antibiotic Action
    RESEARCH HIGHLIGHTS Nature Reviews Microbiology | AOP, published online 26 November 2012; doi:10.1038/nrmicro2931 ANTIMICROBIALS Leaky barrier boosts antibiotic action The nascent polypeptide exit tun‑ Even after exposure to 100‑fold the the drug), the chimeric protein by- nel (NPET), which accommodates minimum inhibitory concentration passed erythro­mycin. This ability was the newly synthesized proteins as they of erythromycin, protein production preserved when several synonymous physiochemical make their way out of the bacterial continued at ~6% of the normal codon substitutions were introduced properties of ribosome, is the target of macrolide level, and strikingly, telithromycin in the hns segment, showing that it is antibiotics. It was generally assumed treatment permitted protein synthe­ the amino acid sequence of the nas‑ the N terminus that these drugs inhibit bacterial sis at ~25% of the normal level. cent peptide, rather than the mRNA determine growth by causing a global arrest in Two-dimensional gel electrophoresis sequence, that accounts for drug whether a protein synthesis; however, a new revealed that many of the synthesized evasion. Furthermore, the protein protein can study now reveals that macrolides proteins were drug specific, indicat‑ HspQ, which contains an N terminus permit translation of a distinct subset ing that the chemical structure of the resembling that of H‑NS, was also circumvent of proteins, and that this could be macrolide determined the spectrum capable of by-passing erythromycin. the macrolide even more detrimental to the cell. of proteins synthesized. Together, these data suggest that the barrier. Macrolides bind to a narrow So what features of the protein physiochemical properties of the region of the NPET and were previ‑ define its ability to by-pass the drug? N terminus determine whether a ously believed to block the passage Mass spectrometry of the synthesized protein can circumvent the macrolide of all proteins.
    [Show full text]
  • Ketek, INN-Telithromycin
    authorised ANNEX I SUMMARY OF PRODUCT CHARACTERISTICSlonger no product Medicinal 1 1. NAME OF THE MEDICINAL PRODUCT Ketek 400 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 400 mg of telithromycin. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Light orange, oblong, biconvex tablet, imprinted with ‘H3647’ on one side and ‘400’ on the other. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications authorised When prescribing Ketek, consideration should be given to official guidance on the appropriate use of antibacterial agents and the local prevalence of resistance (see also sections 4.4 and 5.1). Ketek is indicated for the treatment of the following infections: longer In patients of 18 years and older: • Community-acquired pneumonia, mild or moderate (see section 4.4). • When treating infections caused by knownno or suspected beta-lactam and/or macrolide resistant strains (according to history of patients or national and/or regional resistance data) covered by the antibacterial spectrum of telithromycin (see sections 4.4 and 5.1): - Acute exacerbation of chronic bronchitis, - Acute sinusitis In patients of 12 years and older: • Tonsillitis/pharyngitis caused by Streptococcus pyogenes, as an alternative when beta lactam antibiotics are not appropriateproduct in countries/regions with a significant prevalence of macrolide resistant S. pyogenes, when mediated by ermTR or mefA (see sections 4.4 and 5.1). 4.2 Posology and method of administration Posology The recommended dose is 800 mg once a day i.e. two 400 mg tablets once a day. In patients of 18 years and older, according to the indication, the treatment regimen will be: - Community-acquired pneumonia: 800 mg once a day for 7 to 10 days, Medicinal- Acute exacerbation of chronic bronchitis: 800 mg once a day for 5 days, - Acute sinusitis: 800 mg once a day for 5 days, - Tonsillitis/pharyngitis caused by Streptococcus pyogenes: 800 mg once a day for 5 days.
    [Show full text]
  • AMEG Categorisation of Antibiotics
    12 December 2019 EMA/CVMP/CHMP/682198/2017 Committee for Medicinal Products for Veterinary use (CVMP) Committee for Medicinal Products for Human Use (CHMP) Categorisation of antibiotics in the European Union Answer to the request from the European Commission for updating the scientific advice on the impact on public health and animal health of the use of antibiotics in animals Agreed by the Antimicrobial Advice ad hoc Expert Group (AMEG) 29 October 2018 Adopted by the CVMP for release for consultation 24 January 2019 Adopted by the CHMP for release for consultation 31 January 2019 Start of public consultation 5 February 2019 End of consultation (deadline for comments) 30 April 2019 Agreed by the Antimicrobial Advice ad hoc Expert Group (AMEG) 19 November 2019 Adopted by the CVMP 5 December 2019 Adopted by the CHMP 12 December 2019 Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Categorisation of antibiotics in the European Union Table of Contents 1. Summary assessment and recommendations .......................................... 3 2. Introduction ............................................................................................ 7 2.1. Background ........................................................................................................
    [Show full text]
  • Yeast Glycosylation Mutants Are Sensitive to Aminoglycosides
    Proc. Natl. Acad. Sci. USA Vol. 92, pp. 1287-1291, February 1995 Cell Biology Yeast glycosylation mutants are sensitive to aminoglycosides NETA DEAN Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794-5215 Communicated by William J. Lennarz, State University of New York Stony Brook, NY, September 30, 1994 (received for review July 13, 1994) ABSTRACT Aminoglycosides are a therapeutically im- tants and their genetic analyses will be described elsewhere.) portant class of antibiotics that inhibit bacterial protein syn- Surprisingly, two mutants were isolated that are defective in very thesis and a number of viral and eukaryotic functions by early steps of glycosylation that take place in or before the blocking RNA-protein interactions. Vanadate-resistant Sac- endoplasmic reticulum (ER). The isolation of mutants with de- charomyces cerevisiae mutants with defects in Golgi-specific fects in early steps in the glycosylation pathway suggested that glycosylation processes exhibit growth sensitivity to hygro- hygromycin B sensitivity is not due to defects in Golgi-specific mycin B, an aminoglycoside [Ballou, L., Hitzeman, R. A., functions. To understand how a molecule that binds to RNA Lewis, M. S. & Ballou, C. E. (1991) Proc. Nall. Acad. Sci. USA impinges upon glycosylation within the secretory pathway, I ex- 88,3209-3212]. Here, evidence is presented that glycosylation amined the effect of aminoglycosides on the growth character- is, in and of itself, a key factor mediating aminoglycoside istics ofyeast glycosylation mutants. In the present work, I report sensitivity in yeast. Examination ofmutants with a wide range the results of experiments that demonstrate that aminoglycoside of glycosylation abnormalities reveals that all are sensitive to hypersensitivity is due, at least in part, to defects in glycosylation.
    [Show full text]
  • Antibiotic Resistance and Typing of the Methicillin-Resistant Staphylococcus Aureus Clones in Kuwait Hospitals, 2016–2017 Samar S
    Boswihi et al. BMC Microbiology (2020) 20:314 https://doi.org/10.1186/s12866-020-02009-w RESEARCH ARTICLE Open Access Antibiotic resistance and typing of the methicillin-resistant Staphylococcus aureus clones in Kuwait hospitals, 2016–2017 Samar S. Boswihi, Edet E. Udo* and Wadha AlFouzan Abstract Background: Methicillin-resistant Staphylococcus aureus (MRSA) belong to diverse genetic backgrounds that differ in antibiotic resistance. Knowledge of the local clonal composition of MRSA strains is important for patients’ management and for designing effective control and eradication methods. The aim of this study was to compare the antibiotic resistance patterns and genotypic characteristics of MRSA isolates obtained in public hospitals in Kuwait in 2016 and 2017 for changes in their resistance patterns and clonal composition. Methods: A total of 4726 MRSA isolates obtained in 2016–2017 from clinical specimens in Kuwait public hospitals were characterized using antibiogram, SCCmec typing, spa typing and DNA microarray. Results: The isolates expressed resistance to fusidic acid (52.9%), kanamycin (41.6%), gentamicin (32.5%) and erythromycin (36.2%). The prevalence of high-level mupirocin resistance decreased from 3.7% in 2016 to 2.4% in 2017, while the proportion of resistance to other antibiotics remained relatively stable. A total of 382 spa types were detected with eight spa types, t688 (N = 547), t304 (N = 428), t860 (N = 394), t127 (N = 306), t044 (N = 230), t311 (N = 243), t223 (N = 184) and t002 (N = 181) constituting 53.1% of the MRSA isolates in 2016–2017. Of the 3004 MRSA isolates obtained in 2016 (N = 1327) and 2017 (N = 1677) selected for DNA microarray analysis, 26 clonal complexes (CCs) were identified.
    [Show full text]
  • Topical Antibiotics for Impetigo: a Review of the Clinical Effectiveness and Guidelines
    CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL Topical Antibiotics for Impetigo: A Review of the Clinical Effectiveness and Guidelines Service Line: Rapid Response Service Version: 1.0 Publication Date: February 21, 2017 Report Length: 23 Pages Authors: Rob Edge, Charlene Argáez Cite As: Topical antibiotics for impetigo: a review of the clinical effectiveness and guidelines. Ottawa: CADTH; 2017 Feb. (CADTH rapid response report: summary with critical appraisal). ISSN: 1922-8147 (online) Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document.
    [Show full text]
  • Dissecting the Ribosomal Inhibition Mechanism of a New Ketolide Carrying an Alkyl-Aryl Group at C-13 of Its Lactone Ring Marios G
    Dissecting the ribosomal inhibition mechanism of a new ketolide carrying an alkyl-aryl group at C-13 of its lactone ring Marios G. Krokidis, Ourania N. Kostopoulou, Dimitrios L. Kalpaxis, George P. Dinos To cite this version: Marios G. Krokidis, Ourania N. Kostopoulou, Dimitrios L. Kalpaxis, George P. Dinos. Dissect- ing the ribosomal inhibition mechanism of a new ketolide carrying an alkyl-aryl group at C-13 of its lactone ring. International Journal of Antimicrobial Agents, Elsevier, 2010, 35 (3), pp.235. 10.1016/j.ijantimicag.2009.11.002. hal-00556385 HAL Id: hal-00556385 https://hal.archives-ouvertes.fr/hal-00556385 Submitted on 16 Jan 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: Dissecting the ribosomal inhibition mechanism of a new ketolide carrying an alkyl-aryl group at C-13 of its lactone ring Authors: Marios G. Krokidis, Ourania N. Kostopoulou, Dimitrios L. Kalpaxis, George P. Dinos PII: S0924-8579(09)00511-1 DOI: doi:10.1016/j.ijantimicag.2009.11.002 Reference: ANTAGE 3179 To appear in: International Journal of Antimicrobial Agents Received date: 20-7-2009 Accepted date: 3-11-2009 Please cite this article as: Krokidis MG, Kostopoulou ON, Kalpaxis DL, Dinos GP, Dissecting the ribosomal inhibition mechanism of a new ketolide carrying an alkyl-aryl group at C-13 of its lactone ring, International Journal of Antimicrobial Agents (2008), doi:10.1016/j.ijantimicag.2009.11.002 This is a PDF file of an unedited manuscript that has been accepted for publication.
    [Show full text]
  • Mitochondria and Antibiotics: for Good Or for Evil?
    biomolecules Review Mitochondria and Antibiotics: For Good or for Evil? Juan M. Suárez-Rivero † , Carmen J. Pastor-Maldonado † , Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza and José A. Sánchez-Alcázar * Andalusian Center for Developmental Biology (CABD-CSIC-Pablo de Olavide University) and Center for Biomedical Network Research on Rare Diseases, Carlos III Health Institute, 41013 Seville, Spain; [email protected] (J.M.S.-R.); [email protected] (C.J.P.-M.); [email protected] (S.P.-C.); [email protected] (M.Á.-C.); [email protected] (I.V.-G.); [email protected] (M.T.-R.); [email protected] (A.S.-C.); [email protected] (M.M.-C.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Never- theless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes Citation: Suárez-Rivero, J.M.; other to treating severe infections. Notwithstanding, a notorious number of recent studies support Pastor-Maldonado, C.J.; the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or Povea-Cabello, S.; Álvarez-Córdoba, M.; Villalón-García, I.; Talaverón-Rey, mitochondrial diseases.
    [Show full text]
  • Structural Basis for Potent Inhibitory Activity of the Antibiotic Tigecycline During Protein Synthesis
    Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis Lasse Jennera,b,1, Agata L. Starostac,1, Daniel S. Terryd,e, Aleksandra Mikolajkac, Liudmila Filonavaa,b,f, Marat Yusupova,b, Scott C. Blanchardd, Daniel N. Wilsonc,g,2, and Gulnara Yusupovaa,b,2 aInstitut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7104, 67404 Illkirch, France; bUniversité de Strasbourg, F-67084 Strasbourg, France; cGene Center and Department for Biochemistry, University of Munich, 81377 Munich, Germany; dDepartment of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10065; eTri-Institutional Training Program in Computational Biology and Medicine, New York, NY 10065; fMax Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; and gCenter for Integrated Protein Science Munich, University of Munich, 81377 Munich, Germany Edited by Rachel Green, Johns Hopkins University, Baltimore, MD, and approved January 17, 2013 (received for review September 28, 2012) + Here we present an X-ray crystallography structure of the clinically C1054 via a coordinated Mg2 ion (Fig. 1 D and E), as reported relevant tigecycline antibiotic bound to the 70S ribosome. Our previously for tetracycline (2). In addition, ring A of tigecycline + structural and biochemical analysis indicate that the enhanced coordinates a second Mg2 ion to facilitate an indirect interaction potency of tigecycline results from a stacking interaction with with the phosphate-backbone of G966 in h31 (Fig. 1 C–E). We also nucleobase C1054 within the decoding site of the ribosome.
    [Show full text]
  • Nature Nurtures the Design of New Semi-Synthetic Macrolide Antibiotics
    The Journal of Antibiotics (2017) 70, 527–533 OPEN Official journal of the Japan Antibiotics Research Association www.nature.com/ja REVIEW ARTICLE Nature nurtures the design of new semi-synthetic macrolide antibiotics Prabhavathi Fernandes, Evan Martens and David Pereira Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events.
    [Show full text]