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US 20200017460A1 IN (19 ) United States ( 12 ) Patent Application Publication (10 ) Pub. No.: US 2020/0017460 A1 STIERLE et al. (43 ) Pub . Date : Jan. 16 , 2020 (54 ) 16 -METHYL -OXACYCLOHEXADECAN - 2 - ONE Related U.S. Application Data AND 16 -METHYL - AZACYCLOHEXADECAN - 2 -ONE (60 ) Provisional application No. 62 /473,910 , filed on Mar. DERIVATIVES AS ANTIMICROBIAL 20 , 2017 . AGENTS (71 ) Applicant: THE UNIVERSITY OF MONTANA , Publication Classification Missoula , MT (US ) (51 ) Int. Ci. CO7D 313/00 (2006.01 ) (72 ) Inventors : Andrea STIERLE , Missoula , MT A61P 31/04 (2006.01 ) (US ) ; Donald STIERLE , Missoula , MT C07D 405/04 (2006.01 ) (US ) ; Nigel PRIESTLEY , Alberton , C07D 491/044 ( 2006.01 ) MT (US ) (52 ) U.S. CI. CPC C07D 313/00 ( 2013.01) ; C07D 491/044 (73 ) Assignee : THE UNIVERSITY OF MONTANA , ( 2013.01) ; CO7D 405/04 ( 2013.01) ; A61P Missoula , MT (US ) 31/04 ( 2018.01 ) ( 21 ) Appl. No .: 16 /495,312 (57 ) ABSTRACT (22 ) PCT Filed : Mar. 20 , 2018 16 -membered macrolide compounds inhibit growth of vari (86 ) PCT No.: PCT /US2018 /023332 ous microbial species and have utility in the treatment of $ 371 ( c ) ( 1 ) , systemic or topical microbial infections, including methicil ( 2 ) Date : Sep. 18 , 2019 lin -resistant strains (Formula I) . CO2H ?? , O: Din -CO2H -CO2H BPL 76 ?? BPL 88 .CO2H CO2H CO2H -?? "OH BPL 81/ A26771B BPL 77 BPL 78 COZH ?? , ?? HO "OH BPL 84 BPL 79 CO2H CO2H HO "" OH HO CH2OH BPL 86 BPL 98 Patent Application Publication Jan. 16 , 2020 Sheet 1 of 12 US 2020/0017460 A1 6 FIG . 1A similiki : ????** ??????? FIG . 1B i enester reggaet **** 075 adecan withhandelt FIG . 1C Patent Application Publication Jan. 16 , 2020 Sheet 2 of 12 US 2020/0017460 A1 CO2H ?? , -CO2H CO2H HO BPL 76 HO BPL 88 CO2H CO2H CO2H OH " OH BPL 81/ A26771B BPL 77 BPL 78 CO2H ?? , HO ?? 'OH BPL 84 BPL 79 CO2H CO2H ?? " OH HO CH2OH BPL 86 BPL 98 FIG . 2A Patent Application Publication Jan. 16 , 2020 Sheet 3 of 12 US 2020/0017460 A1 R110 5 CO2H 0 15 2 Ri Disse O CO2R8 " R ? R ? BPL76 R7, R8 , R11 = H BPL81 R2 = H , R3 = H Methylated BPL76 R7, R11 = H , R8 = CH3 BPL77 R2 = OH , R3 = H Acetylated BPL76 R ?,R11 = Ac, R ' = CH3 BPL78 R2 = H , R3 = OH BPL88 R ?, R8 = H ,R11 = COCH2CH2CO2H R110 R120 "R ? O R1 BPL84 R ' = CH3, R², R12 = H , R11 = COCH2CH2CO2H BPL79 R1 = CH3, R2 = OH , R11,1 R12 = H Acetylated BPL79 R ' = CH3, R2 = OAC, R11, R12 = Ac Chiral BPL79 R1 = CH3, R2 = Ror S OMTPA, R11 , R12 = Ror SMTPA BPL86 R ' = CH3, R2 = OH , R11 = COCH2CH2CO2H , R 12 = H BPL 98 R1 = CH2OH , R2 = H , R11 = COCH2CH2CO2H , R 12 = OH , FIG . 2B Patent Application Publication Jan. 16 , 2020 Sheet 4 of 12 US 2020/0017460 A1 un HY H I H OR HO 4 A H S H B I. x 1' OH H R102C FIG . 2C Patent Application Publication Jan. 16 , 2020 Sheet 5 of 12 US 2020/0017460 A1 cz FIG . 2D MTPA - O H -0.05 ? + 0.23 +I -0.07 H + 0.9 MTPA - O ? O - APTM H - 1.17 +0.15 + 0.7 + 0.49 FIG . 2E Patent Application Publication Jan. 16 , 2020 Sheet 6 of 12 US 2020/0017460 A1 220 *** ci FIG . 2F ?? , HOC. ?? , HO HO Loy BPL 94 BPL 95 BPL 96 FIG . 2G Patent Application Publication Jan. 16 , 2020 Sheet 7 of 12 US 2020/0017460 A1 Meo ACO Meo BPL 81 Butyl - succinate BPL 81 5 -MeO BPL 81 5 - OAC BPL 81 2,3 - Cycloprop , 5 -MeO Meo ?? , Meo Me , N BPL 81 lactam , b - 5 -MeO BPL 81 lactam , a - 5 -MeO BPL 81 , 2 -Me , 5 -MeO Fac BPL 81 2 - trifluoroethylthioether Meo dihydro - BPL81, 5 -MeO Ph . NAC .N Meo BPL 81 Butyl est , 2 -phen - ox -ethylamine ' N Meo BPL 81 Butyl est , 2 -piperazine BPL 81,2,3 - epoxide , 5 -MeO SO2 Meo ?? . dh - BPL 81, 2 - phenylsulfonether BPL 81 5 - OH dh -BPL 81 , 2 - phenylthioether BPL 81 4,5 - imidazole BPL 81 Butyl est , 2,3 -pyrazole FIG . 3 Patent Application Publication Jan. 16 , 2020 Sheet 8 of 12 US 2020/0017460 A1 BPL76(50uM) BPL76(250uM) 06300992769 FIG . 4A Patent Application Publication Jan. 16 , 2020 Sheet 9 of 12 US 2020/0017460 A1 Www BPL 76 (50PM ) Fluorescence Aux BPL 76 (250pm ) LaFIG . 4B Patent Application Publication Jan. 16 , 2020 Sheet 10 of 12 US 2020/0017460 A1 8 6 26 B.anthracis UM 64 250 26 >400 50> C,albicans 250 125 250>> 13 UM 32 FIG.5 16 125 3 26 UMug/mL 250 Wwe? ??? 3 6 13709aureus( Staphylococcus 8 8 125 BPL88 BPL81 Patent Application Publication Jan. 16 , 2020 Sheet 11 of 12 US 2020/0017460 A1 CefazoliaDoxycycline Levofloxacia ErythromyciaClindamycin MCJamh) VancomycinErythromycia FIG.6 wy 3 2 6 BPL81BPL76Description www 2 ww HA-MRSA Patent Application Publication Jan. 16 , 2020 Sheet 12 of 12 US 2020/0017460 A1 32 22 532 > 32 $13:48 68 > >63 338 00 fagratis 16.30 2.00 180 2.00 230 *30 200 200 64.30 STANICE 16:00 200 4130 200 2:00 200 200 00* 18:00 Este 2013 200 50 5.50 203 10 3290 08 35393ãos 732 22:00 3836 16:00 16:00 $63 FIG.7 239 30 8.00 30 2.00 1.30 100 100 360 100 22.00 60 230 2.00 2:03 081 14083 1.00 10 200 30 00 0 09 St 200 1.00 OS0 100 OSO VO 2013 3200 OPU81Butylest,2. Datube 921Butyest,20 NeoVer581,2BP: 5.MenCyclapos, BP:81,23*oxicke BYL81,2,5xxide 3981Butyk. 28de 30803a5 BE81Dutyust, BPL814,5midazole ploetasnë B2B3.0 BBP31 (3881 sulfonetherahenyi 1881.nodihydro- 388033 HPL81 SU008ate plentylingelser DB22 deBar Veo Neo US 2020/0017460 A1 Jan. 16 , 2020 1 16 -METHYL -OXACYCLOHEXADECAN - 2 - ONE [0007 ] Compounds described herein may represent a new AND class of macrolide antibiotics useful for treating microbial 16 -METHYL - AZACYCLOHEXADECAN - 2 -ONE infections and inhibiting microbial growth . Conventional DERIVATIVES AS ANTIMICROBIAL macrolide antibiotics produced by bacterial species are AGENTS polypropionate in nature . BPL 76 and related compounds are polyacetate derived . Conventional bacterially derived CROSS - REFERENCE TO RELATED macrolides are active because of specific sugar moieties that APPLICATION ( S ) interact within the ribosome to block bacterial protein syn [ 0001 ] This application claims the benefit of U.S. Provi thesis . BPL 76 and analogs lack all sugar moieties and do not sional Patent Application No. 62/ 473,910 , filed on Mar. 20 , interfere with bacterial protein synthesis . 2017 , the entire contents of which are fully incorporated [ 0008 ] In one aspect, the invention provides a compound herein by reference . of formula ( I ) , or pharmaceutically acceptable salt thereof, TECHNICAL FIELD [0002 ] The invention relates to novel 16 -membered macrolide compounds and pharmaceutically acceptable salts thereof, their use in the treatment of systemic or topical R3 microbial infections, and methods of inhibiting microbial growth . X ! R2 BACKGROUND R1 [ 0003 ] Macrolide antibiotics are important therapeutic agents and are considered to be one of the safest antibiotic treatments available . Macrolide compounds are character wherein ized by the presence of a macrocyclic lactone ring, which [0009 ] Xl is O or NH ; can vary from 12 to 16 atoms, known as a macrolide ring, [ 0010 ] Riis C - alkyl, C -- haloalkyl, -C -zalkylene -OH , and usually one or more sugar chains is attached to the ring . or Cj- zalkylene- OC1- alkyl ; Generally , macrolides inhibit protein synthesis in bacteria by [ 0011 ] R² is hydrogen , OH , OC1- alkyl, OC (O )C reversibly binding to the P site of the 50S unit of the 4alkyl, -OC (O ) C ( CF3 ) (OCH ) Ph , NH , NHC -alkyl , ribosome, thereby interrupting the growth of polypeptides. -N ( C - alkyl ) 2, - NHC( O ) C - alkyl , N ( C -alkyl ) C [0004 ] Macrolide antibiotics such as erythromycin , ( 0 ) C1-4alkyl, SH , SC1- alkyl , or SC ( O )C1 - alkyl; clarithromycin , and azithromycin have been used widely to [ 0012] R is hydrogen , OH , OC1_4alkylOC -alkyl, OC ( O )C1 combat diseases caused by gram -positive pathogens and 4alkyl , NH2, -NHC1-4alkyl, N (C1-4alkyl ) 2 , NHC fastidious gram -negative pathogens . The popularity of this ( 0 ) C1-4alkyl, -N (C1 1 - alkyl) C ( O )C1 - alkyl, SH , SC1 class of antibiotics is largely due to their spectrum of 4alkyl, or SC ( O )C1-4alkyl ; activity . Macrolide antibiotics generally share a similar [0013 ] L ' is range of activities against many strains of streptococci, staphylococci , clostridia , corynebacteria , listeria , haemo philus sp ., moxicella , and Neisseria meningitidis . Clarithro mycin and azithromycin are more active than erythromycin against several gram negative bacteria as well as Myco plasma pneumonia , Helicobacter pylori , Toxoplasma gon dii , cryptosporidia and several atypical mycobacteria . Minund [ 0005 ] Unfortunately , the widespread use and misuse of macrolides , and many other types of antibiotics , catalyzed the emergence of antimicrobial resistant strains . Among gram - positive bacteria , antibiotic resistant Staphylococcus and Enterococcus species pose the biggest threat . Certain gram -negative bacteria are becoming increasingly resistant ht to nearly all of the antibiotic drug options available , creating situations reminiscent of the pre -antibiotic era . Although [0014 ] X7 is H2 or 0 ; overall antifungal resistance is still fairly low , many infec [0015 ] R4 is hydrogen or methyl ; tions caused by the fungus Candida no longer respond to [0016 ] R?is hydrogen , SC1- alkyl, -SC1-4haloalkyl, or common antifungal medications . It is of critical importance S_C alkylene -CH ( R ) X to develop and provide new drugs with broad -spectrum [0017 ] R? is - SC - alkyl, SC )-- haloalkyl, -S ( O ) , - G !, activity , particularly against the ever increasing list of drug -NR - C1- zalkylene - O - G ' , or G ?; resistant microbial species.
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  • Two-Component Signal Transduction System Saers Positively Regulates Staphylococcus Epidermidis Glucose Metabolism

    Two-Component Signal Transduction System Saers Positively Regulates Staphylococcus Epidermidis Glucose Metabolism

    Hindawi Publishing Corporation e Scientific World Journal Volume 2014, Article ID 908121, 12 pages http://dx.doi.org/10.1155/2014/908121 Research Article Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism Qiang Lou,1 Yijun Qi,1 Yuanfang Ma,1 and Di Qu2 1 Laboratory of Cellular and Molecular Immunology, Henan University, Kaifeng 475004, China 2 Key laboratory of Medical Molecular Virology of Ministry of Education and Ministry of Public Health, Institute of Medical Microbiology and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China Correspondence should be addressed to Yuanfang Ma; [email protected] and Di Qu; [email protected] Received 30 August 2013; Accepted 21 November 2013; Published 23 January 2014 Academic Editors: D. Maiorano, H. Okamura, and M. Shiraishi Copyright © 2014 Qiang Lou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE) combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS). Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated.
  • Comparative Genomic Analysis of the Genus Staphylococcus Including

    Comparative Genomic Analysis of the Genus Staphylococcus Including

    Suzuki et al. BMC Genomics 2012, 13:38 http://www.biomedcentral.com/1471-2164/13/38 RESEARCH ARTICLE Open Access Comparative genomic analysis of the genus Staphylococcus including Staphylococcus aureus and its newly described sister species Staphylococcus simiae Haruo Suzuki1, Tristan Lefébure1,2, Paulina Pavinski Bitar1 and Michael J Stanhope1* Abstract Background: Staphylococcus belongs to the Gram-positive low G + C content group of the Firmicutes division of bacteria. Staphylococcus aureus is an important human and veterinary pathogen that causes a broad spectrum of diseases, and has developed important multidrug resistant forms such as methicillin-resistant S. aureus (MRSA). Staphylococcus simiae was isolated from South American squirrel monkeys in 2000, and is a coagulase-negative bacterium, closely related, and possibly the sister group, to S. aureus. Comparative genomic analyses of closely related bacteria with different phenotypes can provide information relevant to understanding adaptation to host environment and mechanisms of pathogenicity. Results: We determined a Roche/454 draft genome sequence for S. simiae and included it in comparative genomic analyses with 11 other Staphylococcus species including S. aureus. A genome based phylogeny of the genus confirms that S. simiae is the sister group to S. aureus and indicates that the most basal Staphylococcus lineage is Staphylococcus pseudintermedius, followed by Staphylococcus carnosus. Given the primary niche of these two latter taxa, compared to the other species in the genus, this phylogeny suggests that human adaptation evolved after the split of S. carnosus. The two coagulase-positive species (S. aureus and S. pseudintermedius) are not phylogenetically closest but share many virulence factors exclusively, suggesting that these genes were acquired by horizontal transfer.