DOCSLIB.ORG

Elution Profiles of Tobramycin and Vancomycin from High-Purity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Elution Profiles of Tobramycin and Vancomycin from High-Purity Original Article Journal of Biomaterials Applications 0(0) 1–9 ! The Author(s) 2016 Elution profiles of tobramycin and Reprints and permissions: sagepub.co.uk/journalsPermissions.nav vancomycin from high-purity calcium DOI: 10.1177/0885328216663392 jba.sagepub.com sulphate beads incubated in a range of simulated body fluids JJ Cooper1, H Florance2,3, JL McKinnon1, PA Laycock1 and SS Aiken1 Abstract The aim of this study was to characterise the elution profiles of antibiotics in combination with pharmaceutical grade calcium sulphate beads in phosphate buffered saline and other physiological solutions which more closely mimic the in vivo environment. Synthetic recrystallised calcium sulphate was combined with vancomycin hydrochloride powder and tobramycin sulphate solution and the paste was formed into 3 mm diameter hemispherical beads. Then 2 g of beads were immersed in 2 ml of either phosphate buffered saline, Dulbecco’s Modified Eagle Medium or Hartmann’s solution and incubated at 37C for up to 21 days. At a range of time points, eluent was removed for analysis by liquid chromato- graphy-mass spectrometry (LC-MS). Tobramycin sulphate and vancomycin hydrochloride release was successfully quan- tified against standard curves from solutions eluted in all three physiological media (phosphate buffered saline, Dulbecco’s Modified Eagle Medium and Hartmann’s solution) during incubation with calcium sulphate beads. One hour eluate concentrations were high, up to 2602 mg/ml for tobramycin in phosphate buffered saline and 7417 mg/ml for vancomycin, whereas in DMEM, the levels of tobramycin were 2458 mg/ml and 4401 mg/ml for vancomycin. The levels in HRT were 2354 mg/ml for tobramycin and 5948 mg/ml for vancomycin. The results show highest levels of antibiotic elution over the first 24 h, which gradually diminish over the following 21 days. Keywords Antibiotics, calcium sulphate, elution Introduction now widely applied as an integral part of two-stage The clinical practice of application of antimicrobial treatment of revision arthroplasty as a result of infec- agents at the site of musculoskeletal infections is one tion, in the form of antibiotic-loaded articulated that is being increasingly reported. This ranges from the spacers or beads.5,6 direct infusion of antibiotic into intra-articular spaces Although providing essential load-bearing capabil- following total knee arthroplasty,1 to the intra-site ity, PMMA is a non-resorbing material requiring placement of antibiotic powder to prevent infection surgical removal. For indications where structural following spinal surgery.2,3 Due to the uncertainty over the duration of effective local antimicrobial concentrations with these methods, the combination 1Biocomposites Ltd., Keele Science Park, Staffordshire, UK of antibiotics with implantable materials in order to 2Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, UK enable predictable, longer-term, release profiles is 3 being widely investigated. Exeter Mass Spectrometry Facility, Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK The concept of local antibiotic release as part of an Corresponding author: infection management strategy is not new. Poly-methyl Phillip A Laycock, Biocomposites Ltd., Keele Science Park, Staffordshire methacrylate (PMMA) has been used in combination ST5 5NL, UK. 4 with antibiotics in this manner for over 40 years, and is Email: [email protected] Downloaded from jba.sagepub.com by guest on August 10, 2016 2 Journal of Biomaterials Applications 0(0) integrity is less important than the ability to predictably HRT, also known as Compound Sodium Lactate release antibiotic, the development of absorbable alter- (CSL), is a solution, isotonic with blood, commonly natives has gained momentum in recent years. used post-operatively to replace bodily fluids, especially Applications such as bone void fillers following surgical in situations of high blood loss. HRT has similar ion treatment of osteomyelitis,7–10 dead space management concentrations to those of human blood, hence the in soft tissue following joint revision surgery,11,12 and rationale for administering to patients suffering from diabetic wound care13,14 are amongst those reporting acute blood loss. It is also commonly used to irrigate promising outcomes. wounds during general surgery and arthroscopic proced- Fundamental to the potential utility of these mater- ures as it has compatible physiological properties.30,31 ials is the rate at which they release their antibiotic load while maintaining antimicrobial efficacy. As this is dif- Materials and methods ficult to accurately determine in vivo, the measurement of antibiotic elution is usually determined in vitro. The release of vancomycin hydrochloride and tobra- In the literature, a broad range of variations in mycin sulphate was evaluated to determine the effect in vitro experimental methods are used to determine of the chosen media on eluted levels of antibiotic. antibiotic elution. Methodologies vary in the nature The samples were prepared as beads, loaded with a by which the sample is presented to the solution, ran- fixed concentration of vancomycin hydrochloride and ging from single small beads15–17 to larger cast cylin- tobramycin sulphate. Beads were immersed in physio- ders.18,19 Also, variation occurs in the quantity of logical solutions at 37C, and the rate of antibiotic material tested, the volume into which the sample is elution was measured over time, up to a period of immersed, the volume removed for analysis and the three weeks using liquid chromatography mass spec- eluent sampling intervals.20,21 However, there is limited trometry (LC-MS). data available on the effect of the elution medium on The in vitro conditions executed were intended to the release of antibiotics. Frequently, elution experi- mimic the implantation of calcium sulphate beads in ments use phosphate buffered saline (PBS) as the a small bone defect. The volume fill of 2 g of calcium elution medium, but this has limited similarity to the sulphate beads is comparable to those used clinically in in-vivo environment with respect to composition and a small bone defect. viscosity. In this study, the antibiotics chosen were vanco- Preparation of beads mycin hydrochloride and tobramycin sulphate since these are frequently used together in clinical practice All bead/antibiotic combinations were prepared using as they provide good empiric coverage for a high pro- the SRCS, provided as a powder (alpha calcium sul- portion of both Gram-positive and Gram-negative phate hemihydrate, CaSO4 Á 1/2 H2O) together with pathogens frequently encountered in surgical site infec- an aqueous mixing solution. When mixed, the resultant tions (SSIs). These were combined with a synthetic paste hydrates and sets according to the following recrystallised calcium sulphate (SRCS), (Stimulan reaction Rapid Cure, Biocomposites Ltd, UK), a fully absorb- able implant material that has been reported previously CaSO4 Á 1=2H2O þ 11=2H2O ¼ CaSO4 Á 2H2O 11–13,22–28 in literature in combination with antibiotics. Calcium sulphate hemihydrate þ water The aim of this study was to characterise the elution ¼ profiles of antibiotics in three different media: phos- Calcium sulphate dihydrate phate buffered saline (PBS) and two physiological solutions which more closely mimic the in-vivo environ- The beads were prepared as follows: In a mixing ment, Dulbecco’s Modified Eagle’s medium (DMEM) bowl, vancomycin hydrochloride powder (1 g, Hospira and Hartmann’s Solution (HRT). UK) was blended with SRCS powder (20 g, powder Although DMEM is water based, the presence of contents of Stimulan Rapid Cure, 10cc pack size, bovine serum increases viscosity and the potential for Biocomposites Ltd, UK) for 1 min to produce a homo- protein binding, resulting in a medium more closely genous mixture. This particular calcium sulphate hemi- mimicking the in vivo environment. In a previous hydrate powder is prepared from high purity study where calcium sulphate was used in combination pharmaceutical grade reagents. When blended with with DMEM and Bone marrow stem cells (BMSC), no the hydrating solution, it has a physiologic pH and adverse effects were reported and it was concluded that contains no earth impurities or stearate additives. It is it was a successful combination for bone tissue engin- known that antibiotic solubility and performance can eering in the treatment of long-standing non-union of vary with pH and this is an important and unreported the Tibia.29 variable in many elution studies. Downloaded from jba.sagepub.com by guest on August 10, 2016 Cooper et al. 3 To the blended powders was added tobramycin sul- phase was held at 5% B for 30 s before increasing in phate solution (6 ml, 40 mg/ml, Hospira UK). The con- a linear fashion to 100% over 3.5 min, where it was tents of the bowl were then mixed together for 30 s to then held for 1 min. Column temperature was main- form a smooth paste. The paste was then transferred tained at 30C with a flow rate of 0.25 ml/min. Due into the mould mat to produce hemispherical beads to the size of the study, high throughput methods with a diameter of 3.0 mm. The beads were allowed to (i.e. short gradients with simultaneous detection of all set in the mould for 15 min before removal. compounds) were required to be able to maximise rep- The beads were extracted from the mould once com- lication and minimise the length of time the samples pletely set simply by flexing the mould and were then were left to stand at 4C. To this end, a compromise stored in sealed moisture proof pouches, to prevent on column length and flow rate was required. The pola- drying out, in a refrigerator at 5C overnight. Two rities of the two antibiotics are very different. grams of the moulded antibiotic beads contain 74 mg Tobramycin is a highly polar molecule and not well vancomycin and 18.5 mg tobramycin. retained on reverse phase columns, whereas vanco- mycin is non-polar and well retained.
Load more

Recommended publications
  • WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) A61K 38/08 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 15/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/031213 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 15 May 2015 (15.05.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/000,43 1 19 May 2014 (19.05.2014) US kind of regional protection available): ARIPO (BW, GH, 62/129,746 6 March 2015 (06.03.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors; and TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicants : GELLER, Bruce, L.
    [Show full text]
  • Quantitative Analysis of Spectinomycin and Lincomycin in Poultry Eggs by Accelerated Solvent Extraction Coupled with Gas Chromatography Tandem Mass Spectrometry
    foods Article Quantitative Analysis of Spectinomycin and Lincomycin in Poultry Eggs by Accelerated Solvent Extraction Coupled with Gas Chromatography Tandem Mass Spectrometry Bo Wang 1,2, Yajuan Wang 2,3, Xing Xie 4, Zhixiang Diao 2,3, Kaizhou Xie 2,3,*, Genxi Zhang 2,3 , Tao Zhang 2,3 and Guojun Dai 2,3 1 College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; [email protected] 2 Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China; [email protected] (Y.W.); [email protected] (Z.D.); [email protected] (G.Z.); [email protected] (T.Z.); [email protected] (G.D.) 3 College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China 4 Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing 210014, China; [email protected] * Correspondence: [email protected]; Tel.: +86-139-5275-0925 Received: 30 March 2020; Accepted: 13 May 2020; Published: 18 May 2020 Abstract: A method based on accelerated solvent extraction (ASE) coupled with gas chromatography tandem mass spectrometry (GC-MS/MS) was developed for the quantitative analysis of spectinomycin and lincomycin in poultry egg (whole egg, albumen and yolk) samples. In this work, the samples were extracted and purified using an ASE350 instrument and solid-phase extraction (SPE) cartridges, and the parameters of the ASE method were experimentally optimized. The appropriate SPE cartridges were selected, and the conditions for the derivatization reaction were optimized. After derivatization, the poultry egg (whole egg, albumen and yolk) samples were analyzed by GC-MS/MS.
    [Show full text]
  • Antibiotic Use and Abuse: a Threat to Mitochondria and Chloroplasts with Impact on Research, Health, and Environment
    Insights & Perspectives Think again Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment Xu Wang1)†, Dongryeol Ryu1)†, Riekelt H. Houtkooper2)* and Johan Auwerx1)* Recently, several studies have demonstrated that tetracyclines, the antibiotics Introduction most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals Mitochondria and chloroplasts are ranging from round worms, fruit flies, and mice to human cell lines. Importantly, unique and subcellular organelles that a plant chloroplasts, like their mitochondria, are also under certain conditions have evolved from endosymbiotic - proteobacteria and cyanobacteria-like vulnerable to these and other antibiotics that are leached into our environment. prokaryotes, respectively (Fig. 1A) [1, 2]. Together these endosymbiotic organelles are not only essential for cellular and This endosymbiotic origin also makes organismal homeostasis stricto sensu, but also have an important role to play in theseorganellesvulnerabletoantibiotics. the sustainability of our ecosystem as they maintain the delicate balance Mitochondria and chloroplasts retained between autotrophs and heterotrophs, which fix and utilize energy, respec- multiple copies of their own circular DNA (mtDNA and cpDNA), a vestige of the tively. Therefore, stricter policies on antibiotic usage are absolutely required as bacterial DNA, which encodes for only a their use in research confounds experimental outcomes, and their uncontrolled few polypeptides, tRNAs and rRNAs [1, 3, applications in medicine and agriculture pose a significant threat to a balanced 4]. Furthermore, both mitochondria and ecosystem and the well-being of these endosymbionts that are essential to chloroplasts have bacterial-type ribo- sustain health.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0005722 A1 Jennings-Spring (43) Pub
    US 20090005722A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0005722 A1 Jennings-Spring (43) Pub. Date: Jan. 1, 2009 (54) SKIN-CONTACTING-ADHESIVE FREE Publication Classification DRESSING (51) Int. Cl. Inventor: Barbara Jennings-Spring, Jupiter, A61N L/30 (2006.01) (76) A6F I3/00 (2006.01) FL (US) A6IL I5/00 (2006.01) Correspondence Address: AOIG 7/06 (2006.01) Irving M. Fishman AOIG 7/04 (2006.01) c/o Cohen, Tauber, Spievack and Wagner (52) U.S. Cl. .................. 604/20: 602/43: 602/48; 4771.5; Suite 2400, 420 Lexington Avenue 47/13 New York, NY 10170 (US) (57) ABSTRACT (21) Appl. No.: 12/231,104 A dressing having a flexible sleeve shaped to accommodate a Substantially cylindrical body portion, the sleeve having a (22) Filed: Aug. 29, 2008 lining which is substantially non-adherent to the body part being bandaged and having a peripheral securement means Related U.S. Application Data which attaches two peripheral portions to each other without (63) Continuation-in-part of application No. 1 1/434,689, those portions being circumferentially adhered to the sleeve filed on May 16, 2006. portion. Patent Application Publication Jan. 1, 2009 Sheet 1 of 9 US 2009/0005722 A1 Patent Application Publication Jan. 1, 2009 Sheet 2 of 9 US 2009/0005722 A1 10 8 F.G. 5 Patent Application Publication Jan. 1, 2009 Sheet 3 of 9 US 2009/0005722 A1 13 FIG.6 2 - Y TIII Till "T fift 11 10 FIG.7 8 13 6 - 12 - Timir" "in "in "MINIII.
    [Show full text]
  • The Use of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Graduate School Professional Papers 2010 The seU of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities Joshua Bryant Phillips The University of Montana Let us know how access to this document benefits ouy . Follow this and additional works at: https://scholarworks.umt.edu/etd Recommended Citation Phillips, Joshua Bryant, "The sU e of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities" (2010). Graduate Student Theses, Dissertations, & Professional Papers. 1100. https://scholarworks.umt.edu/etd/1100 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. THE USE OF NATURAL PRODUCT SUBSTRATES FOR THE SYNTHESIS OF LIBRARIES OF BIOLOGICALLY ACTIVE, NEW CHEMICAL ENTITIES by Joshua Bryant Phillips B.S. Chemistry, Northern Arizona University, 2002 B.S. Microbiology (health pre-professional), Northern Arizona University, 2002 Presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemistry The University of Montana June 2010 Phillips, Joshua Bryant Ph.D., June 2010 Chemistry THE USE OF NATURAL PRODUCT SUBSTRATES FOR THE SYNTHESIS OF LIBRARIES OF BIOLOGICALLY ACTIVE, NEW CHEMICAL ENTITIES Advisor: Dr. Nigel D. Priestley Chairperson: Dr. Bruce Bowler ABSTRACT Since Alexander Fleming first noted the killing of a bacterial culture by a mold, antibiotics have revolutionized medicine, being able to treat, and often cure life-threatening illnesses and making surgical procedures possible by eliminating the possibility of opportunistic infection.
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic review and evidence map Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-027935 review only Article Type: Protocol Date Submitted by the 15-Nov-2018 Author: Complete List of Authors: Dobler, Claudia; Mayo Clinic, Evidence-Based Practice Center, Robert D.
    [Show full text]
  • Interventions for Tuberculosis Control and Elimination
    Interventions for Tuberculosis Control and Elimination 2002 Tuberculosis Interventions International Union Against Tuberculosis and Lung Disease Interventions for Tuberculosis Control and Elimination 2002 Hans L Rieder International Union Against Tuberculosis and Lung Disease 68, boulevard Saint Michel, 75006 Paris, France The publication of this guide was made possible thanks to the support of the United States Centers for Disease Control and Prevention, the British Columbia Lung Association, the French Ministry of Foreign Affairs, and the Norwegian Royal Ministry of Foreign Affairs. Editor International Union Against Tuberculosis and Lung Disease (IUATLD), 68 boulevard Saint Michel, 75006 Paris, France Author : H. L. Rieder © International Union Against Tuberculosis and Lung Disease (IUATLD) March 2002 All rights reserved No part of this publication may be reproduced without the prior permis- sion of the authors, and the publisher. ISBN : 2-914365-11-X II Table of contents Acknowledgments. 1 Preface. 3 Introduction . 5 Summary – the role of specific interventions . 9 1. Chemotherapy . 15 Essential drugs . 15 Isoniazid. 17 Rifampicin . 26 Pyrazinamide . 35 Ethambutol . 37 Streptomycin . 41 Thioacetazone . 45 Fixed-dose combinations . 49 Principal prerequisites for an efficacious anti-tuberculosis drug. 50 Early bactericidal activity . 51 Sterilizing activity. 52 Ability to prevent emergence of resistance to the companion drug . 53 Emergence of anti-tuberculosis drug resistance . 54 Effective or functional monotherapy . 55 Monotherapy during sterilization of special populations . 56 Differences in bactericidal activity . 57 Sub-inhibitory concentrations . 57 Differences in post-antibiotic effect (lag phase) . 59 Clinical trials in the treatment of pulmonary tuberculosis . 59 Streptomycin monotherapy . 61 Streptomycin plus para-aminosalicylic acid . 61 Streptomycin plus para-aminosalicylic acid plus isoniazid.
    [Show full text]
  • Oxazolidinone Antibiotics: Chemical, Biological and Analytical Aspects
    molecules Review Oxazolidinone Antibiotics: Chemical, Biological and Analytical Aspects Claudia Foti , Anna Piperno , Angela Scala and Ottavia Giuffrè * Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy; [email protected] (C.F.); [email protected] (A.P.); [email protected] (A.S.) * Correspondence: [email protected] Abstract: This review covers the main aspects concerning the chemistry, the biological activity and the analytical determination of oxazolidinones, the only new class of synthetic antibiotics advanced in clinical use over the past 50 years. They are characterized by a chemical structure including the oxazolidone ring with the S configuration of substituent at C5, the acylaminomethyl group linked to C5 and the N-aryl substituent. The synthesis of oxazolidinones has gained increasing interest due to their unique mechanism of action that assures high antibiotic efficiency and low susceptibility to resistance mechanisms. Here, the main features of oxazolidinone antibiotics licensed or under development, such as Linezolid, Sutezolid, Eperezolid, Radezolid, Contezolid, Posizolid, Tedizolid, Delpazolid and TBI-223, are discussed. As they are protein synthesis inhibitors active against a wide spectrum of multidrug-resistant Gram-positive bacteria, their biological activity is carefully analyzed, together with the drug delivery systems recently developed to overcome the poor oxazolidinone water solubility. Finally, the most employed analytical techniques for oxazolidinone determination in different matrices, such as biological fluids, tissues, drugs and natural waters, are reviewed. Most are based on HPLC (High Performance Liquid Chromatography) coupled with UV-Vis or mass Citation: Foti, C.; Piperno, A.; spectrometer detectors, but, to a lesser extent are also based on spectrofluorimetry or voltammetry.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Antibiotics That Bind to the a Site of the Large Ribosomal Subunit Can Induce Mrna Translocation
    Downloaded from rnajournal.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Antibiotics that bind to the A site of the large ribosomal subunit can induce mRNA translocation DMITRI N. ERMOLENKO,1,5 PETER V. CORNISH,2 TAEKJIP HA,3 and HARRY F. NOLLER4 1Department of Biochemistry and Biophysics and Center for RNA Biology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA 2Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA 3Department of Physics and Howard Hughes Medical Institute, University of Illinois, Urbana, Illinois 61801, USA 4Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, California 95064, USA ABSTRACT In the absence of elongation factor EF-G, ribosomes undergo spontaneous, thermally driven fluctuation between the pre- translocation (classical) and intermediate (hybrid) states of translocation. These fluctuations do not result in productive mRNA translocation. Extending previous findings that the antibiotic sparsomycin induces translocation, we identify additional peptidyl transferase inhibitors that trigger productive mRNA translocation. We find that antibiotics that bind the peptidyl transferase A site induce mRNA translocation, whereas those that do not occupy the A site fail to induce translocation. Using single-molecule FRET, we show that translocation-inducing antibiotics do not accelerate intersubunit rotation, but act solely by converting the intrinsic, thermally driven dynamics of the ribosome into translocation. Our results support the idea that the ribosome is a Brownian ratchet machine, whose intrinsic dynamics can be rectified into unidirectional translocation by ligand binding. Keywords: antibiotics; Brownian ratchet mechanism; mRNA translocation; ribosome INTRODUCTION kle et al.
    [Show full text]
  • Context-Specific Inhibition of Translation by Ribosomal Antibiotics Targeting the Peptidyl Transferase Center
    Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center James Marksa,1, Krishna Kannana,1,2, Emily J. Roncasea,3, Dorota Klepackia, Amira Kefia, Cédric Orellea,4, Nora Vázquez-Laslopa,5, and Alexander S. Mankina,5 aCenter for Biomolecular Sciences, University of Illinois, Chicago, IL 60607 Edited by Peter B. Moore, Yale University, New Haven, CT, and approved September 2, 2016 (received for review August 5, 2016) The first broad-spectrum antibiotic chloramphenicol and one of the translation arrest. How the ribosome can polymerize a segment of newest clinically important antibacterials, linezolid, inhibit protein the leader peptide, if CHL indiscriminately inhibits formation of any synthesis by targeting the peptidyl transferase center of the bacterial peptide bond, remained unclear. ribosome. Because antibiotic binding should prevent the placement of Although CHL is one of the oldest known antibiotics, linezolid aminoacyl-tRNA in the catalytic site, it is commonly assumed that these (LZD) belongs to one of the newest classes of clinically important drugs are universal inhibitors of peptidyl transfer and should readily PTC-targeting protein synthesis inhibitors, the oxazolidinones (Fig. 1). block the formation of every peptide bond. However, our in vitro Genetic, biochemical, and crystallographic evidence showed that LZD experiments showed that chloramphenicol and linezolid stall ribo- binds in the PTC A site, at a location overlapping with the CHL binding somes at specific mRNA locations. Treatment of bacterial cells with pocket. Similar to CHL, LZD directly clashes with the placement high concentrations of these antibiotics leads to preferential arrest of of the aminoacyl moiety of the aa-tRNA, suggesting that the drug translation at defined sites, resultinginredistributionoftheribosomes should indiscriminately inhibit peptidyl transfer reaction (Fig.
    [Show full text]