Antibiotics Currently in Clinical Development
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United States Patent ( 10 ) Patent No.: US 10,561,6759 B2 Griffith Et Al
US010561675B2 United States Patent ( 10 ) Patent No.: US 10,561,6759 B2 Griffith et al. (45 ) Date of Patent : * Feb . 18 , 2020 (54 ) CYCLIC BORONIC ACID ESTER ( 58 ) Field of Classification Search DERIVATIVES AND THERAPEUTIC USES CPC A61K 31/69 ; A61K 31/396 ; A61K 31/40 ; THEREOF A61K 31/419677 (71 ) Applicant: Rempex Pharmaceuticals , Inc. , (Continued ) Lincolnshire , IL (US ) (56 ) References Cited (72 ) Inventors : David C. Griffith , San Marcos, CA (US ) ; Michael N. Dudley , San Diego , U.S. PATENT DOCUMENTS CA (US ) ; Olga Rodny , Mill Valley , CA 4,194,047 A 3/1980 Christensen et al . ( US ) 4,260,543 A 4/1981 Miller ( 73 ) Assignee : REMPEX PHARMACEUTICALS , ( Continued ) INC . , Lincolnshire , IL (US ) FOREIGN PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this EP 1550657 A1 7/2005 patent is extended or adjusted under 35 JP 2003-229277 A 8/2003 U.S.C. 154 ( b ) by 1129 days. (Continued ) This patent is subject to a terminal dis claimer . OTHER PUBLICATIONS Abdel -Magid et al. , “ Reductive Amination ofAldehydes and Ketones ( 21) Appl. No .: 13 /843,579 with Sodium Triacetoxyborohydride: Studies on Direct and Indirect Reductive Amination Procedures ” , J Org Chem . ( 1996 )61 ( 11 ): 3849 ( 22 ) Filed : Mar. 15 , 2013 3862 . (65 ) Prior Publication Data (Continued ) US 2013/0331355 A1 Dec. 12 , 2013 Primary Examiner — Shengjun Wang Related U.S. Application Data (74 ) Attorney, Agent, or Firm — Wilmer Cutler Pickering (60 ) Provisional application No.61 / 656,452 , filed on Jun . Hale and Dorr LLP 6 , 2012 (57 ) ABSTRACT (51 ) Int. Ci. A61K 31/69 ( 2006.01) Method of treating or ameliorating a bacterial infection A61K 31/00 ( 2006.01 ) comprising administering a composition comprising a cyclic (Continued ) boronic acid ester compound in combination with a car ( 52 ) U.S. -
AMR Surveillance in Pharma: a Case-Study for Data Sharingauthor by Professor Barry Cookson
AMR Open Data Initiative AMR Surveillance in Pharma: a case-study for data sharingauthor by Professor Barry Cookson External Consultant to Project eLibrary • Division of Infection and Immunity, Univ. College London ESCMID• Dept. of Microbiology, © St Thomas’ Hospital Background of “90 day Project” Addressed some recommendations of the first Wellcome funded multi-disciplinary workshop (included Pharma Academia & Public Health invitees: 27thauthor July 2017 (post the Davos Declaration): by 1) Review the landscape of existing Pharma AMR programmes, their protocols,eLibrary data standards and sets 2) Develop a "portal" (register/platform) to access currently available AMR Surveillance data ESCMID Important ©to emphasise that this is a COLLABORATION between Pharma and others Overview of Questionnaire Content • General information - including name,author years active, countries, antimicrobials, microorganisms.by • Methodology - including accreditation, methodology for; surveillance, isolate collection, organism identification, breakpointseLibrary used, • Dataset - including data storage methodology, management and how accessed. ESCMID © 13 Company Responses author 7 by 3 3 eLibrary ESCMID © Structure of register Companies can have different ways of referring to their activities: We had to choose a consistent framework. author Companies Companyby 1 Programmes Programme A Programme B eLibrary Antimicrobials 1 2 3 4 5 company’s product comparator company’s product antimicrobials Programmes canESCMID contain multiple studies (e.g. Pfizer has© single -
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. -
Consideration of Antibacterial Medicines As Part Of
Consideration of antibacterial medicines as part of the revisions to 2019 WHO Model List of Essential Medicines for adults (EML) and Model List of Essential Medicines for children (EMLc) Section 6.2 Antibacterials including Access, Watch and Reserve Lists of antibiotics This summary has been prepared by the Health Technologies and Pharmaceuticals (HTP) programme at the WHO Regional Office for Europe. It is intended to communicate changes to the 2019 WHO Model List of Essential Medicines for adults (EML) and Model List of Essential Medicines for children (EMLc) to national counterparts involved in the evidence-based selection of medicines for inclusion in national essential medicines lists (NEMLs), lists of medicines for inclusion in reimbursement programs, and medicine formularies for use in primary, secondary and tertiary care. This document does not replace the full report of the WHO Expert Committee on Selection and Use of Essential Medicines (see The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2019 (WHO Technical Report Series, No. 1021). Licence: CC BY-NC-SA 3.0 IGO: https://apps.who.int/iris/bitstream/handle/10665/330668/9789241210300-eng.pdf?ua=1) and Corrigenda (March 2020) – TRS1021 (https://www.who.int/medicines/publications/essentialmedicines/TRS1021_corrigenda_March2020. pdf?ua=1). Executive summary of the report: https://apps.who.int/iris/bitstream/handle/10665/325773/WHO- MVP-EMP-IAU-2019.05-eng.pdf?ua=1. -
Cyslabdan, a New Potentiator of Imipenem Activity Against Methicillin-Resistant Staphylococcus Aureus, Produced by Streptomyces Sp
J. Antibiot. 61(1): 7–10, 2008 THE JOURNAL OF ORIGINAL ARTICLE ANTIBIOTICS Cyslabdan, a New Potentiator of Imipenem Activity against Methicillin-resistant Staphylococcus aureus, Produced by Streptomyces sp. K04-0144 II. Biological Activities Atsushi Fukumoto, Yong-Pil Kim, Hideaki Hanaki, Kazuro Shiomi, Hiroshi Tomoda, Satoshi O¯ mura Received: October 5, 2007 / Accepted: December 4, 2007 © Japan Antibiotics Research Association Abstract Cyslabdan produced by Streptomyces sp. K04- 0144 was found to potentiate imipenem activity against methicillin-resistant Staphylococcus aureus (MRSA). The MIC value of imipenem against MRSA was reduced from 16 to 0.015 mg/ml in combination with cyslabdan. Study on anti-MRSA activity of other typical antibiotics in combination with cyslabdan showed that the potentiating activity was limited to b-lactam antibiotics. Furthermore, among b-lactam antibiotics, the activity of carbapenems Fig. 1 Structure of cyslabdan. was most remarkably poteintiated by cyslabdan. Keywords cyslabdan, imipenem potentiator, cyslabdan including potentiation of imipenem activity methicillin-resistant Staphylococcus aureus, MRSA, against MRSA are described. Streptomyces sp. K04-0144, b-lactam Materials and Methods Introduction Materials During our screening for potentiators of imipenem activity The following materials were purchased from commercial against methicillin-resistant Staphylococcus aureus sources: Cloxacillin (ICN Biomedicals), ampicillin (Wako), (MRSA) from microbial metabolites, cyslabdan (Fig. 1) cefalexin (Wako), cefazolin (Wako), ciprofloxacin (Wako), was isolated from the culture broth of Streptomyces sp. vancomycin (Wako), tetracycline (Wako), biapenem (Meiji K04-0144. The compound has a labdane-type diterpene Seika), streptomycin (Meiji Seika), meropenem (Sumitomo skeleton connecting with an N-acetylcysteine via thioether Pharmaceuticals), panipenem (Sankyo), penicillin G linkage [1]. In this study, the biological activities of (Sigma), cefotaxime (Sigma), cefmetazole (Sigma), and S. -
WO 2010/025328 Al
(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 4 March 2010 (04.03.2010) WO 2010/025328 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US2009/055306 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 28 August 2009 (28.08.2009) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/092,497 28 August 2008 (28.08.2008) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): FOR¬ GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, EST LABORATORIES HOLDINGS LIMITED [IE/ ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, —]; 18 Parliament Street, Milner House, Hamilton, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Bermuda HM12 (BM). -
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. -
Intracellular Penetration and Effects of Antibiotics On
antibiotics Review Intracellular Penetration and Effects of Antibiotics on Staphylococcus aureus Inside Human Neutrophils: A Comprehensive Review Suzanne Bongers 1 , Pien Hellebrekers 1,2 , Luke P.H. Leenen 1, Leo Koenderman 2,3 and Falco Hietbrink 1,* 1 Department of Surgery, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; [email protected] (S.B.); [email protected] (P.H.); [email protected] (L.P.H.L.) 2 Laboratory of Translational Immunology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; [email protected] 3 Department of Pulmonology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands * Correspondence: [email protected] Received: 6 April 2019; Accepted: 2 May 2019; Published: 4 May 2019 Abstract: Neutrophils are important assets in defense against invading bacteria like staphylococci. However, (dysfunctioning) neutrophils can also serve as reservoir for pathogens that are able to survive inside the cellular environment. Staphylococcus aureus is a notorious facultative intracellular pathogen. Most vulnerable for neutrophil dysfunction and intracellular infection are immune-deficient patients or, as has recently been described, severely injured patients. These dysfunctional neutrophils can become hide-out spots or “Trojan horses” for S. aureus. This location offers protection to bacteria from most antibiotics and allows transportation of bacteria throughout the body inside moving neutrophils. When neutrophils die, these bacteria are released at different locations. In this review, we therefore focus on the capacity of several groups of antibiotics to enter human neutrophils, kill intracellular S. aureus and affect neutrophil function. We provide an overview of intracellular capacity of available antibiotics to aid in clinical decision making. -
Chemical Properties Biological Description Solubility Information
Data Sheet (Cat.No.T6411) Biapenem Chemical Properties CAS No.: 120410-24-4 Formula: C15H18N4O4S Molecular Weight: 350.39 Appearance: N/A Storage: 0-4℃ for short term (days to weeks), or -20℃ for long term (months). Biological Description Description Biapenem is a 1-beta-methylcarbapenem antibiotic with a wide range of antibacterial activity. Biapenem has similar antibacterial activity to that of imipenem, but is more stable against human renal dehydropeptidase-I and with less neurotoxicity. Targets(IC50) Others: None In vitro Biapenem has activity comparable to those of Imipenem and Meropenem against all groups of anaerobes with MICs for 90% of the strains tested of 0.06 to 2 mg/mL. Biapenem is more active than ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin, cefoxitin, cefotaxime, and ceftriaxone. Biapenem is also active against all of the B. capillosus, Prevotella, Clostridium, and Eubacterium strains and anaerobic cocci tested. [1] Biapenem shows broad antibacterial activity against both Gram-positive and Gram-negative clinical isolates. [2] Biapenem is found to be approximately as active as imipenem, inhibiting 90% of isolates of most species at concentrations within one dilution of the MIC of imipenem for 90% of the isolates. [3] In vivo Biapenem results in significantly fewer viable bacteria than in the lungs of control mice. Biapenem prevents the progression of lung inflammation, including alveolar neutrophil infiltration and hemorrhage. Biapenem significantly prolongs survival and reduces the number of viable bacteria -
Reflection Paper on the Use of Macrolides, Lincosamides And
14 November 2011 EMA/CVMP/SAGAM/741087/2009 Committee for Medicinal Products for Veterinary Use (CVMP) Reflection paper on the use of macrolides, lincosamides and streptogramins (MLS) in food-producing animals in the European Union: development of resistance and impact on human and animal health Draft agreed by Scientific Advisory Group on Antimicrobials (SAGAM) 2-3 June 2010 Adoption by CVMP for release for consultation 10 November 2010 End of consultation (for comments) 28 February 2011 Agreed by Scientific Advisory Group on Antimicrobials (SAGAM) 22 September 2011 Adoption by CVMP 12 October 2011 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. Reflection paper on the use of macrolides, lincosamides and streptogramins (MLS) in food-producing animals in the European Union: development of resistance and impact on human and animal health CVMP recommendations for action Macrolides and lincosamides are used for treatment of diseases that are common in food producing animals including medication of large groups of animals. They are critically important for animal health and therefore it is highly important that they are used prudently to contain resistance against major animal pathogens. In addition, MLS are listed by WHO (AGISAR, 2009) as critically important for the treatment of certain zoonotic infections in humans and risk mitigation measures are needed to reduce the risk for spread of resistance between animals and humans. -
Antibiotics Currently in Clinical Development
A data table from Feb 2014 Antibiotics Currently in Clinical Development As of February 2014, there are at least 45 new antibiotics1 with the potential to treat serious bacterial infections in clinical development for the U.S. market. The success rate for drug development is low; at best, only 1 in 5 candidates that enter human testing will be approved for patients.* This snapshot of the antibiotic pipeline will be updated periodically as products advance or are known to drop out of development. Please contact Rachel Zetts at [email protected] or 202-540-6557 with additions or updates. Cited for Potential Development Known QIDP4 Drug Name Company Drug Class Activity Against Gram- Potential Indication(s)5 Phase2 Designation? Negative Pathogens?3 New Drug Application Acute bacterial skin and skin structure Oritavancin The Medicines Company Glycopeptide Yes (NDA) submitted infections New Drug Application Acute bacterial skin and skin structure Dalbavancin Durata Therapeutics Lipoglycopeptide Yes (NDA) submitted infections NDA submitted (for Acute bacterial skin and skin structure acute bacterial skin infections, hospital acquired bacterial Tedizolid Cubist Pharmaceuticals Oxazolidinone Yes and skin structure pneumonia/ventilator acquired bacterial infection indication) pneumonia ACHN-975 Phase 1 Achaogen LpxC inhibitor Yes Bacterial infections Acute bacterial skin and skin structure infections6, methicillin-resistant Fabl inhibitor (AFN-1252 AFN-1720 Phase 1 Affinium Pharmaceuticals Staphylococcus aureus (MRSA) pulmonary pro-drug) infections -
Interactions of Biapenem with Active-Site Serine and Metallo
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1995, p. 1300–1305 Vol. 39, No. 6 0066-4804/95/$04.0010 Copyright q 1995, American Society for Microbiology Interactions of Biapenem with Active-Site Serine and Metallo-b-Lactamases ANTONIO FELICI,1 MARIAGRAZIA PERILLI,1 BERNARDETTA SEGATORE,1 NICOLA FRANCESCHINI,1 DOMENICO SETACCI,1 ARDUINO ORATORE,1 STEFANIA STEFANI,2 MORENO GALLENI,3 1,4 AND GIANFRANCO AMICOSANTE * Dipartimento di Scienze e Tecnologie Biomediche e di Biometria,1 Cattedra di Chimica Biologica e di Enzimologia,4 Universita` degli Studi dell’Aquila, I-67010 Coppito (L’Aquila), and Istituto di Microbiologia, Universita` di Catania, Catania,2 Italy, and Laboratoire d’Enzymologie, Centre d’Inge´nierie des Prote´ines, Institut de Chimie, Universite´ de Lie`ge, 4000 Lie`ge, Belgium3 Received 14 December 1994/Returned for modification 20 February 1995/Accepted 6 April 1995 Biapenem, formerly LJC 10,627 or L-627, a carbapenem antibiotic, was studied in its interactions with 12 b-lactamases belonging to the four molecular classes proposed by R. P. Ambler (Philos. Trans. R. Soc. Lond. Biol. Sci. 289:321–331, 1980). Kinetic parameters were determined. Biapenem was readily inactivated by metallo-b-lactamases but behaved as a transient inhibitor of the active-site serine enzymes tested, although with different acylation efficiency values. Class A and class D b-lactamases were unable to confer in vitro resistance toward this carbapenem antibiotic. Surprisingly, the same situation was found in the case of class B enzymes from Aeromonas hydrophila AE036 and Bacillus cereus 5/B/6 when expressed in Escherichia coli strains. It has been clearly shown that bacterial resistance to b-lac- which is able to inactivate all b-lactam antibiotics except az- tam antibiotics is often a multifactorial event in which outer treonam (14).