DOCSLIB.ORG

Roxithromycin Degradation by Acidic Hydrolysis and Photocatalysis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Roxithromycin Degradation by Acidic Hydrolysis and Photocatalysis Analytical Methods Roxithromycin degradation by acidic hydrolysis and photocatalysis Journal: Analytical Methods Manuscript ID: AY-ART-03-2014-000708.R2 Article Type: Paper Date Submitted by the Author: 28-May-2014 Complete List of Authors: Kwiecień, Anna; Jagiellonian University, Collegium Medicum, Department of Inorganic and Analytical Chemistry Krzek, Jan; Jagiellonian University, Inorganic and Analytical Chemistry Żmudzki, Paweł; Jagiellonian University, Collegium Medicum, Department of Medicinal Chemistry Matoga, Urszula; Jagiellonian Univeristy, Collegium Medicum, Department of Inorganic and Analytical Chemistry Długosz, Maciej; Jagiellonian University, Faculty of Chemistry Szczubiałka, Krzysztof; Jagiellonian University, Faculty of Chemistry Nowakowska, M; Jagiellonian University, Faculty of Chemistry Page 1 of 23 Analytical Methods 1 2 3 Roxithromycin degradation by acidic hydrolysis and 4 5 6 photocatalysis 7 8 9 10 11 12 13 Anna Kwiecie ń*1 , Jan Krzek 1, Paweł Żmudzki 2, Urszula Matoga 1, Maciej Długosz 3, 14 3 3 15 Krzysztof Szczubiałka , Maria Nowakowska 16 17 18 1 Department of Inorganic and Analytical Chemistry, Jagiellonian University Medical 19 20 College, Faculty of Pharmacy, Medyczna 9, 30-688 Kraków, Poland 21 2 Department of Medicinal Chemistry, Jagiellonian University Medical College, Faculty of 22 23 Pharmacy, Medyczna 9, 30-688 Kraków, Poland 24 3 25 Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 *Corresponding author: 42 43 Dr Anna Kwiecie ń 44 Department of Inorganic and Analytical Chemistry 45 Jagiellonian University, Medical College, Faculty of Pharmacy 46 9 Medyczna Street 47 30-688 Kraków, Poland 48 phone: +48 12 620 54 80 49 fax +48 12 620 54 05 50 e-mail: [email protected] 51 52 53 54 55 56 57 58 59 60 1 Analytical Methods Page 2 of 23 1 2 3 Abstract 4 5 6 The purpose of this work was to study two methods of degradation of roxithromycin; acidic 7 8 hydrolysis and photocatalytic degradation under illumination with near-UV light in the 9 10 11 presence of the TiO 2 photosensitizer. For acidic degradation studies a TLC-densitometric 12 13 method have been developed using TLC aluminium plates precoated with silica gel F 254 and 14 15 the mobile phase composed of methanol-acetone-ammonia 25% (1:14:0.1, v/v/v) which gives 16 17 compact spots for roxithromycin and its degradation products. Photocatalytic degradation 18 19 studies in the presence of TiO were monitored by HPLC . The obtained results have shown 20 2 21 22 that both methods of degradation of roxithromycin are quite efficient. Kinetics of first order 23 24 photocatalytic degradation reaction follows the Langmuir-Hinshelwood theory for 25 26 photocatalytic microheterogeneous systems. The chemical structures of the degradation 27 28 products obtained during acidic degradation and photocatalytic degradation were proposed 29 30 31 based on UPLC-MS/MS technique. The general mechanisms of both processes were 32 33 proposed. 34 35 36 37 38 39 Key words: roxithromycin, degradation studies, kinetic evaluation, TiO 2 photosensitizer, 40 41 quantitative determination, photocatalysis 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 Page 3 of 23 Analytical Methods 1 2 3 Introduction 4 5 Pharmaceuticals are a class of substances which raise increasing environmental 6 7 concern due to their strong bioactivity [1], on one hand, and their growing concentration and 8 9 10 widespread distribution in the environment, on the other [2]. This is, at least in part, due to the 11 12 fact that the pharmaceuticals present in the hospital wastewater are almost always introduced 13 14 untreated to the municipal sewage system and ultimately to the municipal wastewater 15 16 treatment plants (WWTPs). The most potent and harmful pharmaceuticals in the hospital 17 18 wastewater include antibiotics, hormones, enzymes, MRI and X-ray contrast agents, 19 20 21 anesthetics, psychopharmaceuticals, disinfectants and cytostatics [3-5]. Among these 22 23 substances, antibiotics are of special interest because they cause antibiotic resistance of 24 25 (pathogenic) bacteria that is one of the most important challenges of the modern medicine 26 27 worldwide [6]. 28 29 30 Macrolides (MLs) such as erythromycin, clarithromycin, roxithromycin, and 31 32 azithromycin, are the second most important class of antibiotics used in human therapy after 33 34 the β-lactams [7]. Roxithromycin (Roxy), ((E)-erythromycin-9-[O-[(2-methoxyethoxy)- 35 36 methyl]oxime]) is a second generation semi-synthetic macrolide antibiotic derivative of 37 38 39 erythromycin A (Figure 1). It exists in an E-configuration [8]. This molecule is composed of a 40 41 14-membered lactone ring, a desosamine sugar unit and a cladinose sugar unit. A significant 42 43 difference between the structures of both macrolides lies at position 9 of the lactone ring, 44 45 where Roxy has an etheroxime chain instead of a carbonyl group at the same position in 46 47 erythromycin A. 48 49 50 51 52 53 54 55 56 57 58 59 60 3 Analytical Methods Page 4 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Figure 1. Chemical structure of roxithromycin 20 21 22 Roxy is the least active of the 14-membered macrolides having activity against gram- 23 24 positive and gram-negative cocci, gram-positive bacilli and some gram-negative bacilli [9,10]. 25 26 27 Roxy has been frequently detected worldwide in the effluents of WWTPs [11,12], 28 29 surface waters [13], and even a drinking water [14]. Due to the widespread use of Roxy it is 30 31 important to find out its metabolites and the most efficient methods of its degradation before it 32 33 reaches the environment. Oxidative dealkylation of the alkylether side chain, hydrolytic 34 35 36 cleavage of the sugar cladinose, and O-demethylation at the oxime side chain are the major 37 38 metabolic pathways of Roxy in humans [8]. Metabolic isomerization of the oxime is 39 40 stereoselective leading to the formation of Z-oxime isomers [15,16]. 41 42 The acidic hydrolysis of Roxy in simulated gastric fluid (SGF) has been already 43 44 reported [17]. Moreover, the degradation of clarithromycin and Roxy adsorbed on to iron(III) 45 46 47 and manganese(IV) oxides was studied [7]. It was found that the degradation of these MLs 48 49 proceeds both by the hydrolysis of the cladinose sugar and the lactone ring, with the N- 50 51 dealkylation of the amino sugar being the minor pathway. Sorption and transformation of 52 53 MLs on clays have been also described [18]. Biodegradation studies of Roxy in activated 54 55 56 sludge process have shown that hydrolysis of Roxy is negligible and the antibiotic removal 57 58 proceeds mainly through adsorption [19]. 59 60 4 Page 5 of 23 Analytical Methods 1 2 3 The aim of this work was to study the degradation of Roxy by acidic hydrolysis and 4 5 sensitized photodegradation as possible methods of its treatment before it is transferred into 6 7 the environment. We have performed a detailed analysis of the degradation pathway under 8 9 10 these conditions. We also propose the alternative degradation method, a photocatalytic 11 12 degradation of Roxy using TiO 2 dispersion. To the best of our knowledge no papers 13 14 presenting UV-light induced photocatalytic degradation of Roxy sensitized by suspended 15 16 TiO 2 are available in the literature, although systems containing TiO 2 coated on carriers such 17 18 as cenospheres have been reported [20]. 19 20 21 22 23 24 Experimental 25 26 27 28 Apparatus 29 30 31 The degraded Roxy samples were analyzed using UPLC-MS/MS system - ACQUITY 32 33 UPLC and TQD mass spectrometer (Waters Corporation, Milford, MA, USA) and a HPLC 34 35 system composed of a Waters 515 HPLC pump, a 2996 Photodiode Array Detector, and a 717 36 37 Plus Autosampler (Waters Corporation, Milford, MA, USA). TLC analyses were performed 38 39 40 using a TLC Scanner 3 densitometer with Cats 4 software (Camag, Muttenz, Switzerland). 41 42 Irradiations were performed using a Rayonet RPR-100 photoreactor (Southern New England 43 44 Ultraviolet Company, Brandford, CT, USA). Samples were dried using a drying oven with 45 46 natural convection – Binder ED 115/E2 (Binder GmbH, Tuttlingen, Germany) and a muffle 47 48 furnace FCF 5S HM (Czylok, Jastrz ębie Zdrój, Poland). 49 50 51 52 53 54 55 56 57 58 59 60 5 Analytical Methods Page 6 of 23 1 2 3 Dynamic light scattering 4 5 Dynamic light scattering (DLS) of TiO 2 dispersed in water was used to estimate the 6 7 size of the average TiO 2 particle. The measurement was carried out using Malvern Zetasizer 8 9 10 Nano-ZS. Anatase refractive index of 2.55 was used in the calculations. 11 12 13 14 UV-Vis reflectance spectroscopy 15 16 Reflectance spectrum of the TiO 2 powder was acquired using an Ocean Optics 17 18 USB2G5726 spectrophotometer equipped with an AvaLight-DHS lamp and an integration 19 20 21 sphere. The bandgap energy was estimated using Tauc plot. 22 23 24 25 Powder X-Ray diffraction (PXRD) 26 27 The PXRD analyses were carried out to assess the crystal structure of the obtained 28 29 TiO 2. The measurement was carried out using X’PERT PRO diffractometer. Scherrer 30 31 equation was used to approximate the crystallite size: 32 33 34 35 36 37 38 where: 39 40 L – average crystallite size, λ – the wavelength of X-ray radiation, K – shape constant equal to 41 42 43 0.9 for spherical particles, β1/2 – the line broadening at half the maximum intensity, θ - Bragg 44 45 angle 46 47 48 49 Materials and reagents 50 51 52 Roxithromycin - (3R,4S,5S,6R,7R,9R,11S,12R,13S,14R) - 6 - {[(2S,3R,4S,6R) - 4- 53 54 (dimethylamino) - 3 - hydroxy - 6 - methyloxan – 2 - yl]oxy} - 14 - ethyl - 7,12,13 - 55 56 trihydroxy - 4 - {[(2R,4R,5S,6S) - 5 - hydroxy - 4 - methoxy - 4,6 - dimethyloxan - 2 -yl]oxy} 57 58 59 60 6 Page 7 of 23 Analytical Methods 1 2 3 - 3,5,7,9,11,13 - hexamethyl - 10 - (2,4,7 - trioxa - 1 - azaoctan - 1 - ylidene) - 1 - 4 5 oxacyclotetradecan-2-one was purchased from LGC Standards, EPR 1500000, Teddington, 6 7 London, England).
Load more

Recommended publications
  • Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17
    FULL PAPERS DOI:10.1002/adsc.201500250 Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17 Pramod B. Shinde,a,e Hong-Se Oh,b Hyemin Choi,c Kris Rathwell,a Yeon Hee Ban,a Eun Ji Kim,a Inho Yang,a Dong Gun Lee,c David H. Sherman,d Han-Young Kang,b,*and YeoJoon Yoona,* a Department of Chemistry andNano Science,Ewha Womans University,Seoul 120-750, Republic of Korea Fax: (+82)-2-3277-3419;phone:(+ 82)-2-3277-4446;e-mail:[email protected] b Department of Chemistry,Chungbuk National University,Cheongju 361-763, Republic of Korea Fax: (+82)-43-267-2279;phone:(+ 82)-43-261-2305;e-mail:[email protected] c School of Life Sciences,BK21Plus KNU Creative BioResearch Group,College of Natural Sciences,Kyungpook National University,Daehak-ro 80, Buk-gu, Daegu 702-701,Republic of Korea d Department of Medicinal Chemistry,Life Science Institute,DepartmentofChemistry,and Department of Microbiology &Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA e Present address:Institute of Bioinformatics and Biotechnology (IBB), Savitribai Phule Pune University (formerly University of Pune), Pune 411-007, India Received:March 12, 2015; Revised:June 15, 2015;Published online:August 19, 2015 Supporting information for this article is availableonthe WWW under http://dx.doi.org/10.1002/adsc.201500250. Abstract: YC-17 is a12-membered ring macrolide sugars for subsequent glycosylation. Some YC-17 antibiotic producedfrom Streptomyces venezuelae macrolactam analogues were active against erythro- ATCC 15439
    [Show full text]
  • An Effort to Address Antibiotic Resistance
    Desmethyl Analogs of Telithromycin: An Effort to Address Antibiotic Resistance A Dissertation Submitted to the Temple University Graduate Board in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy By Venkata Velvadapu August, 2011 Examining Committee Members: Dr. Rodrigo B. Andrade, Research Advisor, Chemistry Dr. Franklin A. Davis, Committee Chair, Chemistry Dr. William M. Wuest, Committee Member, Chemistry Dr. Kevin C. Cannon, External Committee Member, Chemistry i © by Venkata Velvadapu 2011 All Rights Reserved ii ABSTRACT The development of antibiotic resistance has been an inevitable problem leading to an increased demand for novel antibacterial drugs. To address this need, we initiated a structure-based drug design program wherein desmethyl analogues (i.e., CH 3H) of the 3rd -generation macrolide antibiotic telithromycin were prepared via chemical synthesis. Our approach will determine the biological functions of the methyl groups present at the C-4, C-8 and C-10 position of the ketolide. These structural modifications were proposed based on the structural data interpreted by Steitz and co-workers after obtaining crystal structures of macrolides erythromycin and telithromycin bound to the 50S ribosomal subunits of H.marismortui. Steitz argued that in bacteria, A2058G mutations confer resistance due to a steric clash of the amino group of guanine 2058 with the C-4 methyl group. In turn, we hypothesize that our desmethyl analogs are predicted to address antibiotic resistance arising from this mutation by relieving the steric clash. To readily access the analogs, we proposed to synthesize, 4,8,10-tridesmethyl telithromycin, 4,10-didesmethyl telithromycin, 4,8-didesmethyl telithromycin and 4- desmethyl telithromycin as four targeted desmethyl analogs of telithromycin.
    [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]
  • Synthesis and Biological Investigation of New 400-Malonyl Tethered Derivatives of Erythromycin and Clarithromycin Daniel Sherman,A Liqun Xiong,B Alexander S
    Bioorganic & Medicinal Chemistry Letters 16 (2006) 1506–1509 Synthesis and biological investigation of new 400-malonyl tethered derivatives of erythromycin and clarithromycin Daniel Sherman,a Liqun Xiong,b Alexander S. Mankinb and Artem Melmana,* aDepartment of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel bCenter for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607, USA Received 25 August 2005; accepted 12 December 2005 Available online 4 January 2006 Abstract—A new approach to 400-substituted derivatives of erythromycin and clarithromycin was developed by converting them into corresponding 400-malonic monoesters. Subsequent carbodiimide coupling with alcohols and amines provided new macrolide deriv- atives that are capable of binding to 50S ribosomal subunits and inhibiting protein synthesis in cell-free system. Ó 2005 Elsevier Ltd. All rights reserved. Erythromycin 1a and other macrolide antibiotics X 1 OR (Scheme 1) have been used for the treatment of a variety R 2 of bacterial infections for the past 50 years. Low toxicity R HO NMe2 O 2' and cost as well as low incidence of side effects resulted 3 O R4 O in extensive use of erythromycin both for treatment of O R3 infections and prophylactic purposes.1 The active use 1a R=H, R1=R2=OH, R3=H, R4= cladinose, X= C=O of the drug resulted in a wide spread of macrolide resis- 1b R=Me, R1=R2=OH, R3=H, R4= cladinose, X= C=O tance in a number of pathogenic strains. As an example, 1 2 3 4 1c R=H, R =R =OH, R =H, R = cladinose, X= N(Me)CH2 in Asia the majority (up to 80% in Hong Kong) of Strep- 1 2 3 4 tococcus pneumoniae strains carry resistance to macro- 1d R=H, R =R =OH, R =H, R = cladinose, 2 X= C=NOCH2OCH2CH2OMe lide antibiotics.
    [Show full text]
  • Simultaneous Determination of Various Macrolides by Liquid Chromatography/Mass Spectrometry Youn-Hwan Hwang, Jong-Hwan Lim, Byung-Kwon Park and Hyo-In Yun*
    J. Vet. Sci. (2002), 3(2), 103-108 J O U R N A L O F Veterinary Science Simultaneous Determination of Various Macrolides by Liquid Chromatography/Mass Spectrometry Youn-Hwan Hwang, Jong-Hwan Lim, Byung-Kwon Park and Hyo-In Yun* Division of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University Received J a n . 4, 2002 / Accept ed Ap r . 29, 2002 ABSTRACT7) poultry, those are 0.125 g/kg for erythromycin and 0.1 g/kg for tylosin. In order to monitor macrolide residues, simple, Macrolides are frequently use d in veterinary confirmatory and simultaneous analytical methods are m edicine as therape utic and preve ntive agents for required. various diseases. It is difficult to determine m acrolides Microbiological assays were widely used for determination sim ultaneously w ith conventional m ethods due to of macrolide antibiotics [3, 4]. Unfortunately, these methods their sim ilar structures. A sim ultaneous analysis for could not be used for simultaneous analysis due to lacks of erythrom ycin, roxithrom ycin, tiam ulin and tylosin their specificities. Gas chromatography-mass spectrometry w ith LC/MS has bee n develope d. Se paration w as (GC-MS) supplies good sensitivity and selectivity [5], but pe rform ed on C18 reversed phase colum n. Mobile direct analysis for macrolides antibiotics is difficult because phase w as gradiently flow e d w ith 10 m M am m onium of their thermal labile property and low volatility. acetate and m ethanol. The m ass spectrome ter w as Liquid chromatographic methods have been reported for run in the positive m ode and sele ctive ion monitoring the determination of macrolide antibiotics: UV absorption m ode.
    [Show full text]
  • Strategies for the Synthesis of Glycosylated Small Molecule
    University of Connecticut Masthead Logo OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 4-11-2019 Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds Zachary Cannone University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Cannone, Zachary, "Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds" (2019). Doctoral Dissertations. 2089. https://opencommons.uconn.edu/dissertations/2089 Strategies for the Synthesis of Glycosylated Small Molecule Libraries and New Bioactive Compounds Zachary Cannone Ph.D., University of Connecticut, 2019 Abstract: The synthesis of glycosylated small molecule compound libraries remains a difficult challenge in the field of organic chemistry. Leading techniques are hindered by the requirement of optimization based on substrate, and the generation of non-classical glycoside products. The development of a platform which takes advanced glycoside intermediates and utilizes reactive handles on the aglycone for rapid diversification to final products has been completed in this research. Use of amino sugars, derived from known antibiotics, as the carbohydrate component of final compounds was intended to exploit known binding interactions with biomacromolecules. Final compounds indeed showed ability to inhibit bacterial protein synthesis in vitro and limit growth in culture, suggesting binding interactions were retained. Development of new generations of therapeutics based on current classes of antibiotics remains a primary means of new drug discovery. The aminoglycoside family of antibiotics is no exception to this, as current members of this class show promise of improved pharmacological properties with diversification to their structures. Studies have been conducted but have not addressed novel alkylation patterns on the amino sugar component of these compounds.
    [Show full text]
  • Azalides from Azithromycin to New Azalide Derivatives Stjepan Mutak
    J. Antibiot. 60(2): 85–122, 2007 THE JOURNAL OF REVIEW ARTICLE ANTIBIOTICS Azalides from Azithromycin to New Azalide Derivatives Stjepan Mutak Received: August 22, 2006 / Accepted: January 22, 2007 © Japan Antibiotics Research Association Abstract Azalides are semi-synthetic macrolides, in which a nitrogen atom is introduced into a macrolactone ring via a Beckmann rearrangement. Starting from erythromycin, oximes, depending on the reaction conditions lactams, or bicyclic-imino-ethers were formed, which were further reduced to aminolactones. The cyclic amine 9a- became the precursor for novel, significantly more active derivatives, especially for 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a- homoerythromycin A with the generic name azithromycin. It showed a broad spectrum of antibacterial activity covering all significant bacteria causing respiratory tract infections. The greatest advantages of azithromycin are its unusual pharmacokinetics (high tissue distribution), metabolic stability and high tolerability. These properties have led in recent years to the widespread use of the azalide scaffold for the synthesis of new compounds with advantageous pharmacokinetics. The azalide scaffold possesses an amino and several hydroxyl groups, which could be substituted or transformed to obtain new compounds. Different derivatives were obtained by substitution on the nitrogen but a large variety of derivatives, such as ethers, esters and carbamates, were made by reactions with various hydroxyl groups. Substitutions on both nitrogen and hydroxyl or two hydroxyl groups yielded new, bridged compounds. The 4Љ- hydroxy group was oxidized to 4-oxo-, which was transformed via the oxime to 4-amino, or via epoxide to 4Љ-methylamino compounds. Cleavage of the cladinose sugar and further transformations gave 3-acyl or 3-oxo compounds, which were less active than 14-membered acylides or ketolides.
    [Show full text]
  • Determination of Roxithromycin by Liquid Chromatography/Mass Spectrometry After Multiple-Dose Oral Administration in Broilers
    J. Vet. Sci. (2003), 4(1), 35-39 J O U R N A L O F Veterinary Science Determination of Roxithromycin by Liquid Chromatography/Mass Spectrometry after Multiple-Dose Oral Administration in Broilers Jong-hwan Lim, Byung-kwon Park and Hyo-in Yun* Division of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon, Korea Received J anuary 30, 2003 / Accepted March 28, 2003 Abstract6) in human and veterinary medicine [8]. Several methods have been reported for determination of A highly se nsitive and specific m ethod for the roxithromycin in biological fluids. Microbiological assays in de term ination of roxithrom ycin in broiler tissues by plasma, urine and milk have been reported [4]. However, LC/MS w as de veloped and validated. A dichloro- microbiological assays have several disadvantages in terms m ethane extract of the sam ple w as se parated on C18 of the limit of quantitation, specificity and rapidity. Some reversed-phase colum n w ith acetonitrile-50 m M am - methods based on the reversed-phase HPLC have been m onium acetate (80:20, v/v) as the m obile phase and developed for the qunatitation of roxithtomycin or other analyzed by LC/MS via atm ospheric pressure ioni- macrolides. UV absorption [2, 11, 14], fluorescence and elec- zation/e lectrospray ionization inte rface . The lim it of trochemical detection [3, 5, 13, 15] methods have been used, de tection and lim it of quantitation w ere 1 ng/g and 5 but these methods achieved only relatively high detection ng/g.
    [Show full text]
  • The Crystal Structure of Two Macrolide Glycosyltransferases Provides a Blueprint for Host Cell Antibiotic Immunity
    Corrections BIOCHEMISTRY. For the article ‘‘The crystal structure of two GENETICS. For the article ‘‘Deletion of the orphan nuclear recep- macrolide glycosyltransferases provides a blueprint for host cell tor COUP-TFII in uterus leads to placental deficiency,’’ by antibiotic immunity,’’ by David N. Bolam, Shirley Roberts, Mark Fabrice G. Petit, Soazik P. Jamin, Isao Kurihara, Richard R. R. Proctor, Johan P. Turkenburg, Eleanor J. Dodson, Carlos Behringer, Francesco J. DeMayo, Ming-Jer Tsai, and Sophia Y. Martinez-Fleites, Min Yang, Benjamin G. Davis, Gideon J. Tsai, which appeared in issue 15, April 10, 2007, of Proc Natl Davies, and Harry J. Gilbert, which appeared in issue 13, March Acad Sci USA (104:6293–6298; first published April 2, 2007; 27, 2007, of Proc Natl Acad Sci USA (104:5336–5341; first 10.1073͞pnas.0702039104), the authors note that the e-mail published March 21, 2007; 10.1073͞pnas.0607897104), the au- address for corresponding author Fabrice G. Petit appeared thors note that, in addition to writing the paper, Benjamin G. incorrectly. The correct address is [email protected]. The Davis should be credited with designing the research and online version has been corrected. analyzing the data. The corrected author contributions footnote ͞ ͞ ͞ ͞ appears below. www.pnas.org cgi doi 10.1073 pnas.0703353104 Author contributions: D.N.B., S.R., and M.R.P. contributed equally to this work; D.N.B., M.R.P., B.G.D., G.J.D., and H.J.G. PHYSIOLOGY. For the article ‘‘Night eating and obesity in the designed research; D.N.B., S.R., and M.R.P.
    [Show full text]
  • 1 Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin
    1 Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin Through Carbenoid Functionalization A Thesis Presented to the Honors Tutorial College, Ohio University In Partial Fulfillment Of the Requirements for Graduation From the Honors Tutorial College With the degree of Bachelor of Science in Chemistry By: Andrea J. Oliver May 2019 2 This thesis is titled Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin Through Carbenoid Functionalization By: Andrea J. Oliver Has been approved by The Honors Tutorial College And the Department of Chemistry and Biochemistry Dr. Mark C. McMills Associate Professor, Thesis Advisor ______________________________ Dr. Lauren McMills Director of Studies, Chemistry ______________________________ Cary Roberts Frith Interim Dean, Honors Tutorial College ______________________________ 3 ABSTRACT OLIVER, ANDREA J., May 2019, Chemistry Diversification of Antibiotic Scaffolds Spiramycin and Roxithromycin Through Carbenoid Functionalization Thesis Advisor: Dr. Mark C. McMills Despite the constant development of new antibiotics, difficulties are encountered almost immediately through the development of antibiotic resistance. Researchers must constantly work to develop new antibiotics, while diversifying old antibiotic structures in order to avoid a global crisis caused by the generation of multidrug resistant organisms. This work described in this thesis attempts to diversify inexpensive, macrolide antibiotic scaffolds such as roxithromycin and spiramycin through the removal of sugar moieties, the functionalization of the existing ring and other structural changes. 4 ACKNOWLEDGEMENTS I would like to thank Dr. Mark McMills and Dr. Lauren McMills for their endless patience and guidance these last four years. I could not have made it this far without the support of two such caring individuals. Thank you for pushing me to try even when I was scared and getting me to the next step.
    [Show full text]
  • Macrolides, Ketolides, and Glycylcyclines: Azithromycin, Clarithromycin, Telithromycin, Tigecycline
    Macrolides, Ketolides, and Glycylcyclines: Azithromycin, Clarithromycin, Telithromycin, Tigecycline a,b, b JerryM.Zuckerman, MD *, Fozia Qamar, MD , a,b Bartholomew R.Bono, MD KEYWORDS Macrolides Ketolides Glycylcyclines Antimicrobials Review Erythromycin, the first macrolide antibiotic discovered, has been used since the early 1950s for the treatment of upper respiratory tract and skin and soft tissue infections caused by susceptible organisms, especially in patients who are allergic to penicillin. Several drawbacks, however, have limited the use of erythromycin, including frequent gastrointestinal intolerance and a short serum half-life. Advanced macrolide antimi- crobials synthesized by altering the erythromycin base have resulted in compounds with broader activity, more favorable pharmacokinetics and pharmacodynamics, and better tolerability. In 1991 and 1992, the US Food and Drug Administration (FDA) approved two of these agents, clarithromycin (Biaxin) and azithromycin (Zithro- max), for clinical use. Since their introduction, these advanced macrolides have been used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and infections caused by Helicobacter pylori and Mycobacterium avium complex (MAC). Ketolides, a new class of macrolides, share many of the characteristics of the advanced macrolides. Their in vitro spectrum of activity also includes gram-positive organisms (Streptococcus pneumoniae, Streptococcus pyogenes) that are macrolide a Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA b Division of Infectious Diseases, Department of Medicine, Albert Einstein Medical Center, Klein Building, Suite 331, 5501 Old York Road, Philadelphia, PA 19141, USA * Corresponding author. Division of Infectious Diseases, Department of Medicine, Albert Einstein Medical Center, Klein Building, Suite 331, 5501 Old York Road, Philadelphia, PA 19141. E-mail address: [email protected] (J.M.
    [Show full text]
  • Manipulating Nature's Sugar Biosynthetic Machineries for Glycodiversification of Macrolides: Recent Advances and Future Pros
    Pure Appl. Chem., Vol. 79, No. 4, pp. 785–799, 2007. doi:10.1351/pac200779040785 © 2007 IUPAC Manipulating nature’s sugar biosynthetic machineries for glycodiversification of macrolides: Recent advances and future prospects* Christopher J. Thibodeaux and Hung-wen Liu‡ Division of Medicinal Chemistry, College of Pharmacy, Department of Chemistry and Biochemistry, and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA Abstract: Changing the sugar structures and glycosylation patterns of natural products is an effective means of altering the biological activity of clinically useful drugs. Several recent strategies have provided researchers with the opportunity to manipulate sugar structures and to change the sugar moieties attached to these natural products via a biosynthetic approach. In this review, we explore the utility of contemporary in vivo and in vitro methods to achieve natural product glycodiversification. This study will focus on recent progress from our labo- ratory in elucidating the biosynthesis of D-desosamine, a deoxysugar component of many macrolide antibiotics, and will highlight how we have engineered the D-desosamine biosyn- thetic pathway in Streptomyces venezuelae through targeted disruption and heterologous ex- pression of the sugar biosynthetic genes to generate a variety of new glycoforms. The in vitro exploitation of the substrate flexibility of the endogenous D-desosamine glycosyltransferase (GT) to generate many non-natural glycoforms will also be discussed. These experiments are compared with recent work from other research groups on the same topics. Finally, the sig- nificance of these studies for the future prospects of natural product glycodiversification is discussed. Keywords: biosynthesis; glycodiversification; unusual sugars; macrolides; antibiotics.
    [Show full text]