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THAI HIEN TAI AIUS009790495B2 AI AI AI UN TATA MONITOR (12 ) United States Patent ( 10 ) Patent No. : US 9 ,790 ,495 B2 Geller et al. (45 ) Date of Patent: Oct . 17 , 2017 ( 54 ) ANTISENSE ANTIBACTERIAL COMPOUNDS 8 , 299 ,206 B2 10 /2012 Fox et al. AND METHODS 8 , 314 , 072 B2 11/ 2012 Geller et al. 8 ,536 , 147 B2 * 9 / 2013 Weller . A61K 48 / 00 514 /44 A @(71 ) Applicants :Bruce L . Geller, Corvallis , OR (US ) ; 9 , 249 ,243 B2 * 2 /2016 Weller .. .. .. A61K 48 /00 David Greenberg , Coppell , TX (US ) 2004 /0029129 A1 * 2 /2004 Wang ** * * * . .. CO7K 14 / 195 435 /6 . 18 @(72 ) Inventors : Bruce L . Geller, Corvallis , OR (US ) ; 2005 / 0288246 Al 12/ 2005 Iversen et al. David Greenberg, Coppell , TX (US ) 2006 / 0241075 A1 * 10 /2006 McSwiggen . .. .. C12N 15 / 1138 514 /44 A @ 2006 /0270621 A1* 11/ 2006 Christiano .. .. A61K 9 /0014 ( 73 ) Assignees : Oregon State University , Corvallis , 514 /44 R OR (US ) ; Board of Regents , The 2007 / 0049542 A1 3 / 2007 Geller et al. University of Texas System , Austin , 2008 / 0194463 A1 8 / 2008 Weller et al . TX (US ) 2010 / 0016215 A1 1 / 2010 Moulton et al. 2010 / 0234281 A1 9 / 2010 Weller et al. ( * ) Notice: Subject to any disclaimer, the term of this 2010 /0261777 A1 * 10 /2010 Shaw . .. .. .. .. .. C12N 15 / 102 514 /44 R patent is extended or adjusted under 35 2012 /0040460 A1 * 2 /2012 Rigoutsos . .. C12N 15 / 111 U . S . C . 154 (b ) by 0 days . 435 /375 2012 / 0122769 A1 5 / 2012 Iversen (21 ) Appl. No. : 14 /713 , 857 2012 / 0213663 A1 8 /2012 Atieh et al. 2012 /0289457 A 11/ 2012 Hanson (22 ) Filed : May 15 , 2015 2012 / 0296087 AL 11/ 2012 Sinha et al. 2013 /0197220 Al 8 /2013 Ueda (65 ) Prior Publication Data 2016 /0106857 A14 / 2016 Geller et al . US 2015 /0361425 A1 Dec . 17 , 2015 FOREIGN PATENT DOCUMENTS KR 10 - 2013 - 0005208 * 1 / 2013 Related U . S . Application Data KR 2013 /0005208 A 1 / 2013 ( 60 ) Provisional application No . 61 / 994 , 750 , filed on May WO WO 93 /01286 A2 1 / 1993 WO WO 2004 /097017 A2 11/ 2004 16 , 2014 , provisional application No . 62 /099 , 046 , WO WO 2006 / 085973 A2 8 / 2006 filed on Dec . 31 , 2014 , provisional application No . WO WO 2008 /008113 AL 1 /2008 62/ 129 ,746 , filed on Mar. 6 , 2015 . (Continued ) (51 ) Int . Cl. C12N 15 / 11 ( 2006 . 01 ) OTHER PUBLICATIONS C12N 15 / 113 ( 2010 .01 ) Youngblood et al. Bioconjugate Chem 2007 , 18 , 50 -60 . * A61K 4748 ( 2006 . 01 ) KR 10 - 2013 - 0005208 pp . 1 -29 , Machine English Translation . * A61K 38 / 00 ( 2006 .01 ) GenBank 01251363 [KR 1020130005208 - A / 39 : Method and kit for ( 52 ) U . S . CI. detecting carbapenem resistant enterobacteriaceae using real - time CPC . .. C12N 15 / 113 (2013 .01 ) ; A61K 47/ 48246 PCR ] ( retrieved on Oct. 13 , 2015 from http : // www .ncbi . nlm .nih . ( 2013 .01 ) ; A61K 38 / 00 ( 2013 .01 ) ; C12N gov / nucleotide /662699238 ? report = genbank & log $ = nuclalign & blast _ rank = 1 & RID = 1V40 3DGD016 ] Jul . 8 , 2014 ( Jul. 8 , 2014 ) 2310 / 11 (2013 .01 ) ; C12N 2310 /3233 whole doc . ( 2013 .01 ) ; C12N 2310 / 3513 ( 2013 .01 ) ; C12N PCT/ US2015 /031150 , International Search Report and Written 2320 / 50 ( 2013. 01 ) Opinion dated Jan . 14 , 2016 . PCT/ US2015 /031213 , International Search Report and Written (58 ) Field of Classification Search Opinion dated Sep . 2 , 2015 . CPC .. .. C12N 15 / 113 ; C12N 2310 / 11 ; C12N PCT/ US2015 / 000280 , International Search Report and Written 2310 /3233 Opinion dated May 2 , 2016 . See application file for complete search history . Summerton et al. 1997 , " Morpholino antisense oligomers : design , preparation , and properties .” Antisense and Nucleic Acid Drug (56 ) References Cited Development ( 1997 ) ; 7 . 3 : 187 - 195 . PCT/ US2015 /031150 , International Preliminary Report on Patent U . S . PATENT DOCUMENTS ability dated Nov . 22 , 2016 , 11 pages . PCT/ US2015 /031213 , International Preliminary Report on Patent 5 , 034 , 506 A 7 / 1991 Summerton et al. ability dated Nov. 22 , 2016 , 7 pages . 5 , 142 , 047 A 8 / 1992 Summerton et al . 5 , 166 , 315 A 11/ 1992 Summerton et al. Primary Examiner — Brian Whiteman 5 , 185 , 444 A 2 / 1993 Summerton et al. (74 ) Attorney , Agent, or Firm — Cooley LLP 5 ,217 , 866 A 6 / 1993 Summerton et al . 5 , 506 , 337 A 4 / 1996 Summerton et al. (57 ) ABSTRACT 5 , 521, 063 A 5 / 1996 Summerton et al . Provided are antisense morpholino oligomers targeted 5 ,698 ,685 A 12 / 1997 Summerton et al . against bacterial virulence factors such as genes that con 6 , 245 , 747 B1 6 / 2001 Porter et al. tribute to antibiotic resistance or biofilm formation , or genes 6 , 965, 025 B2 11/ 2005 Gaarde et al. associated with fatty acid biosynthesis , and related compo 6 , 969 , 400 B2 11/ 2005 Rhee et al. sitions and methods of using the oligomers and composi 7 ,625 , 873 B2 12 / 2009 Geller et al. 7 , 790 , 694 B2 9 / 2010 Geller et al. tions , for instance , in the treatment of an infected mamma 8 , 067 ,571 B2 11 / 2011 Weller et al. lian subject. B2 12 / 2011 Reeves et al . 38 Claims, 22 Drawing Sheets US 9 ,790 ,495 B2 Page 2 ( 56 ) References Cited FOREIGN PATENT DOCUMENTS WO WO 2009 /005793 A2 1 /2009 WO WO 2009 /064471 A1 5 / 2009 WO WO 2012 /043730 4 / 2012 WO WO 2012 / 064991 Al 5 / 2012 WO WO 2012 / 150960 AL 11 /2012 wo WO2013011072 A1 * 1 / 2013 WO WO 2015 / 175977 A2 11 / 2015 WO WO 2015 / 179249 AL 11 /2015 WO WO 2016 / 108930 A2 7 / 2016 * cited by examiner atent Oct. 17 , 2017 Sheet 1 of 22 US 9 ,790 , 495 B2 Bebe BongebotV . lv 1D FIG.1 1B Direttae baino X bambina - - - - ** 1.4 ** - . ONCH) * UOMO atent Oct. 17 , 2017 Sheet 2 of 22 US 9 ,790 , 495 B2 16 NHASXARXABXKERKYRK . WOW-3269 yhose OSTEO . 2 .O '.'., mer 0 V ** * * * Wis ASTRO O ACHNRICETTEREFRETERXB. CP050305*PPMO P00734PPMO NOVO €63.Tai FIG.1 , . ecsgo « .No Mello « ACHNAXARXARXRRXKXB. OWddS2000 atent Oct. 17 , 2017 Sheet 3 of 22 US 9 ,790 ,495 B2 PPMO#5AdeA-Aba PPMOconcentration(UM) A.baumaniiAYE FIG.2 : :: : : :: : : :: : : :: : : :: : : :: : : :: : :: : : :: : : :: : : :: : : :: : : 10240 512 )ugimi ( MIC Gentamicin atent Oct. 17 , 2017 Sheet 4 of 22 US 9 ,790 ,495 B2 _ UZA32HUEwneg WoWdd . ) mL/ lug Tobramycin MIC 333Ayy?? ???{ SHOWdd €913 # ??? * * IIHWUBAVkuuewnegv * NIOWdd( * * * )mL / g ( Tobramycin MIC LI atent Oct. 17 , 2017 Sheet 5 of 22 US 9 ,790 ,495 B2 . PPMO#5AdeA-Aba illiu...PPMOconcentration(UM) A.baumaniiAYE FIG.4 228328 * X *X6 0 XXXX8 * AX8381983 * * * 1-5.0 )ml / ug ( MIC Tetracycline atent Oct. 17 , 2017 Sheet 6 of 22 US 9 ,790 , 495 B2 DEBOT-13025H0m1andMeropenemco 32 GermanyMDM-1*M0X2 WNOW:PPM 026NDM-1BCTBbaumannii.A Iwn)Ondd FIG.SA 0.5 meningtrate minrdirbti en mann en sammenhiberdrolabilirl bridal willann e med interne concernance internet ) mL/ ug ( Meropenem MIC atent Oct. 17 , 2017 Sheet 7 of 22 US 9 ,790 , 495 B2 .mL1#/PPMOug 8Meropenem BUM +Meropenem e mL /Bug FIG.5B 1#PPMO 1-NDM SUM PPMOScr 24Time alone Ab 100 ml/ CFU 0Time alone Ab atent Oct. 17 , 2017 Sheet 8 of 22 US 9 ,790 , 495 B2 otobolobyOZ PPMO#2concentration(UM) E.coliBCT-B036(NDM1) FIG.6 er atent Oct. 17 , 2017 Sheet 9 of 22 US 9 ,790 , 495 B2 alonePeptide Scr IIIRIIEREIII . PPMo1/??? FIG.7A * PPMOsuhB * Owddddoe ?? ? PPMONo 570 OD U . S . Patent Oct. 17 , 2017 Sheet 10 of 22 US 9 , 790, 495 B2 alonePeptide PPMOScr PPMOcepl FIG.7B PPMOsuhB PPMOacpP PPMONo 570 OD i § atent Oct. 17 , 2017 Sheet 11 of 22 US 9 ,790 ,495 B2 : : : : : FIG.8A : : W U . S . Patent Oct. 17 ,2017 Sheet 12 of 22 US 9 , 790, 495 B2 ????3 ?????????????? ??????? ??? ??? ?????? * ??????? ??? ???? ?????????? ??????? ???? ??? ???? ?????? ?????????? ??? ?????? ??????? ??????? ???????? ?????? US. Patemt o c . 17 , 2017 Sheet 13 of 22 _ US 9, 790, 495 82 ????.????? ?????? ??????????????????????? ?????????? ?????????? 8'ei ? ? ?? ?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? ??????? ???????? ??? ? ? ? ? ? ? ????? U . S . Patent Oct. 17 , 2017 Sheet 14 of 22 US 9 , 790, 495 B2 (w /or ezL )Usweq01 + dos 11111111111 )mL /pg 64( Tobramycin +cepl cepi EstablishedBiofilmBreakdown FIG.9 )mL /pg 128 (Tobramycin +Scr )uglmL 64 (Tobramycin +Ser Scr PPMONo wa within mimin F01 CFU U . S . Patent Oct. 17 , 2017 Sheet 15 of 22 US 9 , 790, 495 B2 NY 2840> 16UM SUM AUM 3KM12 29#PPM0RXB ;).RFFacpr ( 28#PPMO -acpp 2627#ifcopPPMO PPMO -acpp 17#PPMO -hacpp 16#PPMO ! acp 15#PPMO -acpp 1824#acppPPMO PPMO -acpp 25#PPMO -acpp FIG.10 23#PPMO -acpP 27*PPMO -opp # 20PPMO121#PPMO -acphacpP 19#PPMQ -acpp MARS970 (35) h why &rexcio(3840-2) Bruitivorans(SH-21 .wpacia(3753) B.parja(1820) B.cepaca(1640-2) B.cpada(2299) R.duloxa(AUD$45) 8,gladiosi(HI2:37) 8.cestocepscia(1513) 8.Qanocepacia(B3 B.cenocepacia(A-245) ,cenocepacia(12315) 5.capacia(1882 28363Eacia(3. %.cegada(K43128) B.dolosa(A00158) A.gk?mae(A06208) 8.multivorans($41) pymooniaAUX:34)(B. 8.stabstis(H12230; K.anybifasia(AU0212) B.ambaska(BA4-243 B.cedoooxacia(807 8,canocepacia(K12424) 8.exacePR«X(K56 tmbAULO$4)(cenocepacia8, 8.gadol(AU15937) .multivoransAUD862) 8.stokivorals(844-147) B.multivorans(#12229) pyrodnia)(AUL114B. ?,?ibrfa{Au2 &cæ000-nacia(A137 12728Quba)crocepacia(8. B,multivos2:06AU0267 8.Pyrrocinka(A025 8.stabilisAV26756 8,vietnamlensis(AU01087 s,vietnamiensis(A118839) 24Hvietsensis8kAB. he n : S ' u?rd 0 LIOTÁLI bayS 91 JO TT S1 °06LÝ6 S6 78 22#PPMO T24 191#PPM0 T24 1 Aguo(L?ZVIH )079 B 117 ministráncele intre ense numerose momencie wwdiscovery only)H14277 (BCC TO . mL/ CFU Log FIG.11 . PPM019.T24 A only)2 -K456 (B¢¢ T24 : :: : : : : : : : : : : :: :: : : : : : : : : :: : :: : : : : : : : : : : : : : : : : : : : : : : :: : : : : : : :: : : : : :: : : :: : :: : : : : : :: : :: : . 119 m bestehet LLLLLLL met matinada la con che L .1 2 Webmx only)2-K56 (Bcc TO . ml/ CFU log U . S . Patent Oct.
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    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.
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    Therapeutic Perspective Development of antibiotics for Gram-negatives: where now? Clin. Invest. (2011) 1(2), 211–227 The incidence of infections due to multidrug-resistance pathogens, such as Enterobacteriaceae, Pseudomonas aeruginosa or Acinetobacter spp. has been Matteo Bassetti†1, Francesca increasing. The paucity of antimicrobials active against multidrug- resistance Ginocchio1, Daniele Roberto strains are an important challenge. Novel anti-Gram-negative agents from Giacobbe1 & Malgorzata Mikulska1 old antimicrobial classes include b-lactamase inhibitors, cephalosporins, 1Division of Infectious Diseases, San Martino carbapenems, aminoglycosides, polymyxin analogs, tetracycline and mono- Hospital & University of Genoa, bactams. Among them, b-lactamase inhibitors seem the most promis- L.go R.Benzi 10, 16132 Genova, Italy † ing as they might restore the activity of already known b-lactams against Author for correspondence: Tel.: +39 010 555 5132 b­-lactamase-producing strains. New classes of antimicrobials include bis- Fax: +39 010 353 7680 indoles, boron-containing antibacterial protein-synthesis inhibitors, outer E-mail: [email protected] membrane synthesis inhibitors, antimicrobial peptides and antibiotics targeting novel sites of the 50S ribosomal subunit. Although promising, they are still far from being introduced into clinical practice. Therefore, optimizing the use of current antibiotics and infection control policies are mandatory. Keywords: antimicrobial peptides • ESKAPE • extended-spectrum b-lactamases • metallo-b-lactamases • new b-lactamase inhibitors • new cephalosporins Multidrug resistance (MDR) is defined as nonsusceptibility to one or more antimicrobials in three or more antimicrobial classes, while strains nonsusceptible to all antimicrobials, including polymyxins and tigecycline, are classified as extreme drug-resistant strains [1]. MDR Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings and are especially common and problematic in some intensive care units [2].
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    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2011, p. 4943–4960 Vol. 55, No. 11 0066-4804/11/$12.00 doi:10.1128/AAC.00296-11 Copyright © 2011, American Society for Microbiology. All Rights Reserved. MINIREVIEW Carbapenems: Past, Present, and Futureᰔ Krisztina M. Papp-Wallace,1,2 Andrea Endimiani,1,2,3 Magdalena A. Taracila,2 and Robert A. Bonomo1,2,4,5* Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 441061; Institute for Infectious Diseases, University of Bern 3010, Bern, Switzerland3; and Departments of Medicine,2 Pharmacology,4 and Molecular Biology and Microbiology,5 Case Western Reserve University, Cleveland, Ohio 44106 In this review, we summarize the current “state of the art” of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as “slow substrates” or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This “value-added feature” of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.

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    Acta Pharm. 62 (2012) 305–323 Original research paper DOI: 10.2478/v10007-012-0024-z Quantitative structure-pharmacokinetic relationship (QSPkR) analysis of the volume of distribution values of anti-infective agents from J group of the ATC classification in humans BRUNO LOUIS1 In this study, a quantitative structure-pharmacokinetic 2 VIJAY K. AGRAWAL * relationship (QSPkR) model for the volume of distribu- tion (V ) values of 126 anti-infective drugs in humans was 1 Department of Pharmacy, Sultan d developed employing multiple linear regression (MLR), Qaboos University Hospital artificial neural network (ANN) and support vector re- PO Box 38, Al Khod, Muscat 123 gression (SVM) using theoretical molecular structural des- Oman criptors. A correlation-based feature selection (CFS) was 2 QSAR and Computer Chemical employed to select the relevant descriptors for modeling. Laboratories, A.P.S. University The model results show that the main factors governing Rewa-486003, India Vd of anti-infective drugs are 3D molecular representa- tions of atomic van der Waals volumes and Sanderson ele- ctronegativities, number of aliphatic and aromatic amino groups, number of beta-lactam rings and topological 2D shape of the molecule. Model predictivity was evaluated by external validation, using a variety of statistical tests and the SVM model demonstrated better performance compared to other models. The developed models can be used to predict the Vd values of anti-infective drugs. Keywords: QSPkR, QSPR, structure pharmacokinetic rela- Accepted June 12, 2012 tionship, volume of distribution, ANN, SVM, CFS There is a constant need to develop new anti-infective drug molecules because the antibiotics and antiviral drugs always face a threat of resistance development, which may eventually lead to therapeutic failure.