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`CLINICAL MICROBIOLOGY REVIEWS
`
`VOLUME 12 0 OCTOBER 1999 0 NUMBEFI 4
`
`Betty A. Forbes, Editor in C.-":t'c_f' (2002)
`SUNY Health Science Center
`
`S}-'rocu.s'c, N. Y.
`
`Lynne S. Garcia, Editor (2002)
`UCLA Mctlicai Ccittcr
`Los /lngcies, Calif?
`
`Kenneth D. Thompson, Editor’ (2002)
`Unll»"ii8‘i{}’ of Chicago Medical Comer
`Chicngo_.
`IN.
`
`Judith E. Domer U999}
`Kevin Hansen (2001)
`
`EDITORIAL BOARD
`
`J. Michael Miller (2000)
`Mark LaRocco (2001)
`Daniel F. Sahm (2001)
`
`Steven C. Specter (2000)
`Gregory A. Storch (2001)
`
`Samuel Kaplan, Chrtirmair, PuhrlicnrirJn.r Board
`
`Linda M. Illig, Director. .:'om'.=-ials
`
`Victoria A. Cohen, Proct'uct£on Editor
`
`C!im'cm' i'vt'ici'obr'0i’o_gt-‘ Reviews c0r1s."ders fot'pttb1it.'atr'on both sot':'ct't‘cd amt’ tmso.-’r'cr'tcd revicri=.s' and monographs dealing with cit’ aspects
`of clinical trticrobioiogy. Mrmtt.sc.=t'pts_. proposals. mm’ con'cs;Joito.’encc regora'ing ctiitor't'at' matters shotriri be rtcldi'rr.s'5r!tt' to the Editor in
`C.-’.=.icfi Betty/l. Forbes. Dcptrmncm ofC!t'm'trat'1’ati1oIog)*. SUNYHeaz'tl'r Scicrtcc Ccmcr. 750 Ea.rrAdums' S1,. Sy:'at'trsc. NY i32i0-2339.
`
`Clinical Microbiology Reviews (ISSN 0893-85 I2) is published quarterly (January, April, July, and October). one volume per year.
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`Copyright © 1999, American Society for Microbiology.
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`Clinical
`
`Microbiology
`
`Reviews
`
`A Publicration of the American Society for Microbiology
`
`VOLUME12
`
`o OCTOBER1999 o
`
`NUMBEFI4
`
`CONTENTS/SUMMARIES
`
`Antifungal Agents: Mode of Action, Mechanisms of Resistance, and
`Correlation of These Mechanisms with Bacterial Resistance
`Mahmoud A. Ghannoum and Louis B. Rice .....................
`
`501-517
`
`.S'witmiit}-': The iherettseti use ofn-ittibactet'ittt' {mt} tiittifititgtti ttgents in recent yettizs‘ has i'esttite(."
`iii the a'e1=eh9pmettt of i‘e.s'i_s'tt;-nee to these drugs. The sigi21fic'ei1t c.-iihiem’ impiimtitm of i'est'sttit1ee
`hrts ied to heighteited ittterest in the sttiriy ofritttiiitiembirii re,s'i_s'tt;rttee jioiit dtfetI’itttti1gie5. Areas
`ttddre3.§ect' theittde iiiecimitisms tmde.='t'yihg this re.s'i.s-tcmee.
`i.=ttpi‘01-'ett' iiiethotis to deteet :'esi,v-
`twice when it OL‘Cm'S. aitetmite options‘ for the ttetttmettt of itt_feetiott.v erttiseri by t"(?$i.)'t't’t.iIt‘
`w‘gtttti.<ttits. and stmtegies to p.F'{.'1‘(fti't' aim’ emit.-‘oi’ the emery.;‘ettt:e tin.-:i spremi oft:r.*si,s‘tam'e. ht titis
`.!‘£’1.'i{’H'. the mode of L¢'(.'fi()iI of ai:tt]'imgai.y and their iiteeiittiti.s‘tiis of tesisttmee are zii.¢eit_-med.
`/1riditi0itt'ii:"y, an attempt is made to r1i_s'etis.v the coi'i‘ehitioit between _:"iiti_gzii
`trim’ htteteifrii
`i*e5i.s'tm.=ce. Aittifiittgftirt em? be g!‘I:'J£u‘jJL’(i into three eiasses bttseti on their site 0_f'rteti0i1: ttzoies.
`which inhibit the syttthe.-:i'.': t2fetgo5tet'oi (the mtiiit fitiigei stewi); pot'yene.-a". which ihterttct witii
`fimgti! memhium: .s'temt's ,.rJity.9icoet'teim'r:ttihJ,' and 5-fiuoi'o(}-‘taxi:ze, which hthibits Hi£i'(‘i'0i.?‘:'(Ji{?(.'-
`Iih’fi‘.§.'_1'IIIiIt3.\'i.§‘. Matty citfieretit types Q3"ittcac‘imttisim' eotitribitte to the deveiupmetit ofresisttm(:e
`to rti:tifiri:gtti.€. These iiieehtiitistits im'hta‘e ttheratioit in dmg target, ttitemtiott ii: xteivi bio.s‘yii-
`the.s'i.sj. redttctioit iii the ii?i(3i‘(.‘{.'ii£ii£it' r.'cmeet:ti'ittit)t: of target en.‘-;}'me, tutti 0vet'e.1pi'essiutt Q,f' the
`rmtt}‘lmgt‘.-i (hug trtiget.
`/lhhough the er)ir1pai'i.s0n between the t'?‘t(’(‘ihftt'ti.$‘tt1S of re.s'i.';tcmce to
`tmtt‘JI'}-,titgt:ti5 mid (N?iii)(t('i(.’I'iEIi.\'
`ix iicee.s'.s'ttt'iiy iimited try severrti fi.’(.‘iOi".‘)‘ (hi’fii't(.’(i in the tel-'iew,
`ti
`e0t‘i‘eietioti betweeii the two exim. FOJ"(’,l‘t?fl1phE’, inricitfictttiott of eirzymes which serve as t'(i‘t‘gr;’.i.S'
`for titttimiei'obftii tterioii arid the in 'l-‘O.i1:‘£’i?t1’tIi 0fttrt'ittbi‘ei1epumps in the exttmitm of th'ttg.s' are
`weii chtti‘tt(‘tei'izeci in imth the eti.kai}=tJtic‘ mid pi'0icctiyotie (.'eii.s'.
`
`QFever.
`
`M.1\/[aurin and D.Raoult
`
`.S'wttiiitti}': Q jever is it zo0.Itosi.s‘ with it M.-'o.=':’dwide tt'isti'iimtioti with the e.reepti0it of New
`Zerihtmti. The disertse is trtittseci by (.‘r,=.\'ieihi httrtietii.
`If stt'i:.-thr‘
`ititi‘rt::.'eiittitt.=‘, gt‘flt'.'1—t?('gaii1-'6
`i.3(i('!‘(’t"iIt.'?L Many species oftmimmtiis. birtis, mid tieh'.s' are i'e.ven‘oi.='.s' of C‘. iJitmetii iii tmtitre.
`C. htmtetii i.'l__ii£’(‘ii0tl is most qfteii htteiit iii tiiiimtiis, with petzvisteitt .s't'teci:'iiitg of bacteria into the
`eiwimtimeitt. However‘.
`in feiiirties iiiteiwiitteirt iiigir-ie1'ei sizeeitiiitg OC(‘ttt".'t at the time of par-
`titritiott. with miiiimts of t'Jrietei'irt being t'eiettseti per gnc.-tit of ph'tt."L’t1t‘(t. Hi.ti.=taiis tire ttsitrthy
`t'ttfeetec1 by eotttamiimteti tt(.'.?'(J.5'0i.5‘ _,I‘i'0m {i(JnI(.’.s'ii(.‘ £u'tiHi(ti.§'. pai‘tiettim'i}‘ ctflei' eoiatrtet with
`parti.-rietttfetmties amt their hirtii pi'orhiet$. Aitiwugh ofteiz ri.'[_\‘tttpfO!'tt(tii(‘. Q_fevei'tmt_1-' itittnifevt
`in ittttmms es mi tieute riisetise {nmitit'_\‘ its (1 .s'eh‘1iitiii'teii _feht't'ie iiiitess, pi'ietmioitiri, 0J"il(?p{tt‘ifiS)
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2090 - 3/23
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`Coiitiiztted rm _!E;h’.r)h-'ittg page
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2090 - 3/23
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`Ctmtinneti fi'otn pneeetiittg page
`
`or as a chronic tiisease (tttttittiv etttioeartiitis), espeeiaiht in patients with pre-.-‘ions 1-'tth-‘tihipatity
`and to (t htsser extent in intntttttocontprotnised hosts anti in pt‘egttattt wonten. Speet}ie tiittgttosis
`of Q _t‘e1'er tentains based ttpon seroiag): hnntttnogiobttiitt M (igMj ttaa’ t'gG antiphase U
`tttttihodies are detected’ 2 to 3 weeits ttfter injection with C. bttt'ttetii, whereas the pt'esenee ofigfi
`antiphase I C. btttnetii ttntibodies at titers of 213800 by ntiet'oitntntntof1't.tote.s'eenee is ittdieative
`of eittvttie Q fizver. The tett'a<.y(.'iittes are stiii eottsitieteti the mainstay of'antibiotit: titerapy of
`aettte Q fever. whereas antibiotic‘ t.'wnbittation.\' aa’ntittistereti over pt‘0iattgea' periatis are nee-
`esstn_v to pre1=ettt reiapses in Q feverendaeartiitis ptttients. Aithottgit the pt‘t)teetii=e .'O.i(’ ofQ fever
`1-'aecittttti0n with whoie—eeii extmets has been estabiisheti.
`the popttiation which shonia‘ be
`primariiy vaeeinateti t'entat'tts to he c'iettt'i_'t itietttifieti. Varseittrttiott shottid probabiy he t:0ttsi(i-
`ereti in the popttiation at high risk for Q fever enrioettrtiitis.
`
`New Insights into Human Cryptosporidiosis.
`
`Dougias P. Clark .
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`554-563
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`Sttnttnaty: Ct}:Dtt).Sp0t'itifttiii parvnm is an important cause ofdiamfiett wot‘hiwt'a'e. Ctypto.sp0t'idiatn
`eattses a prttetttiaiiy itfe—threatening tiisease in peopie with AIDS and contribtttes .sigttt',t'ieantiy to
`tttrtthiciity among eitihirett in a'eI-'et'opittg er)ntttt'ies.
`in inttnt.nmer)ntpetent achtits, C.'typtosp0-
`ridinnt is often assoeiateti with waterborne ottthrettks of aettte diarrhea! iiiness. Recent studies
`with htmtan voittttteers have h'tdi('ttI6d that Cty;7tct.spot'idittnt is highiy ittfeetiotts. Diagnosis of
`infection with thi.s' parasite has reiieti on it1etttt]’ication of aeia'—fast ooey.s't.s' in stool; however,
`new imntttttoassay.s or PCR-based assays may increase the .s'ettsiti1=ity of‘ detection. Aithongh the
`meet’-tanism by which Ctj.tpto.s'pt)t'idittnt eattses diarrhea is stih’ poariy tttta'erstoaa', the parasite
`anti the itnntttne response to it probab.-'_v eotnbitte to impair ttbsotptiott and enhance secretion
`within the intestittai tract. intportant genetie studies suggest that humans can he ittfet.'tea' by at
`ieast two genetir.'at'z'y rhstinet types ofCtypto.spot'itiittttt. it-'t'tiet't may vat)’ in vitttienee. This tnay,
`in part. explain the eiinieai vttritthiiity seen in patients with etj.tpto.s'poritiiosis.
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`Plant Products as Antimicrobial Agents.
`
`Marjorie Murphy Cowan .
`
`.
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`Sttnthtary: 'The. use of anti .5‘{’ttt'{'h' _f:)r thttgs and tiietttty sttppietnents (i6’t'i1‘(ftif'Ut?T plants have
`ttt.‘t.'eien:ttea.' in recent years. Etitnctphartttttcroiogists, hotttttists,
`tttiembioiogists, anti natttrat'-
`prothtets chemists ate eontbittg the Earth jbr pit}-‘taeitetttic'ttis' and “ietttis" which eottia’. be
`de1-'eiopedfat' treatntent ofittfeetiotts diseases. Whiie 25 to 50% of ettrrent p'h'(tt?tItI(.'(:’ttfiCt'i'iS ate
`a'eri:-‘ea’ fi'1’)J"-P1 piants. none ate used as tttttintierabiat's. Traa'ititnttti heaiers have iottg axed piants
`to pt'erent or care infi'etioas conditions.’ Western nteziieine is ttyittg to dttpiieate their saecesses.
`Pittttts are rich in a wide 1'ariet_v 0fsect)ttdttty ntetaboiites, such as tannins, terpenoids, ttikaioids,
`and fiat-'onoia's. which have heen fintmi in vitro to have atttinticrabitti properties. Tt'ti.s' review
`ttttentpts to snmmarize the ettrrent stains afbotttttieai .§‘Ct‘E€t‘tit!g efibwts. as weii as in vivo studies
`of their e_1§I‘"et‘ti1-'et1es.s' and toxicity. The strt.tett.n'e anti arttintierohiai properties 0f,'Ji'tytoehetnieais
`are aiso athiresseti. Sinee many of these eotnpottttds are earnen.ti;.-' airttiiabie as ttnregtn'ateti
`hotattieai preparation.s‘ anti their use by the pahiie is ittcreasittg rapitiiy. eiinieians need to
`trtmsider the eon.seqttettee.s' 0}" patients seif—ttteth'eating with these pteparations.
`
`Antifungal Activities of Antineoplastic Agents: Saccharomyces cerevisiae
`as a Model System To Study Drug Action.
`Maria E. Cardenas,
`M. Cristina Cruz, Maurizio Del Poeta, Namjin Chung, John R.
`Perfect, and Joseph
`
`583«6ll
`
`SttttIt?t(tt}'.' Reeent eitoitttiottttty sttttiies reveai that mieroorgattistns it-tehtdittg yeasts and fimgi
`are more <'iosez’_}-‘ rehttetl to raantmais than was ptei—=iottsi_v appreeiateti. Possibht as a conse-
`quence, ntany tttttttt'ai—pt‘0a'aet toxins that hat.-"e ttntitttit.-rohiai activity are aiso toxic" to t‘tm't"tt—
`ntaiian eeiis. Whiie this ntakes it tiij}it.'ttit to diseoi-‘er ttttttfttttgtti agents without toxic side efiieets,
`it aiso has entthied tietaiiezi studies oft1’t'ttg action in .-ample genetic ntariei .sy:stett1s'. We teview
`here sttniies ah the ahttfnngai actions of ttt'ttitte0phtsntie agents. Topics covered inehtcie the
`ntet.'hanisnts of action of initih.-'tors of tapoisontet'tt.se.s'
`i attti ii.‘
`the intmtrnt)sappt'essattts
`rapantyeitt, ex-'eit)_\p0rit't A. and FK5(){t.' the pitosphtttiafyiitmsitot’ 3-ichtase inhibitor worttnannitt:
`the (tttgi0gt:'tt£’.\'i.3' inhibitors fitmagiiiitt anti Olfittiicitt.‘ the HSP90 im'tihitot' geitittttantyeitt: anti
`agents that inhibit .s',ttitittgt)iipt'ti ntettthtiiisnt. ht generai.
`these natttrai ptttthtets itthihit target
`proteins t1‘Ot't.S‘t’t‘l’t’t’i frrnn ntierootgattisnts to hnntans. These sttahes itigitiight the potetttiai of
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`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2090 - 4/23
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`Cotttitttttrti an ftn'io1«1.'ittg page
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2090 - 4/23
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`(.'otttt'ntte.:t fnotn pnrcetltttg page
`
`t'ttlC‘t'OOtgttttls'ttt5' as seteetting tools to (.’ltt(.'l(l(tt‘L’ the ntecltantstns of aettott ofttovel pltttt't'Ttt£t(.'0-
`logical ttgents with ttntqtte efl"ects ttgttt'm't sper_'tfit' tttttttttnttlttttt cell types, tneltta't'ng t't£’Upltt.St‘t(.'
`cells. ht atltlittott. this ttntth'.si.s' suggests that tattttteoplttsttc agents and tlet't1-=tttl1‘es might _fintt'
`not-'el tttthetttiotts in the tretttment of fungal tttfectthtts. for H-'ht't:h few ctg'nts are preset-ttljr‘
`t.t‘1-’ttll{tl)l£’_.
`to,1't'e.it_v rentttitts a serious concern, and tlrttg t'est'sttntce ts etttet;t;tttg.
`
`Methods for Subtyping and Molecular Comparison of Human Viral
`Genomes.
`Max Arens .
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`6l2—626
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`Stttnntatj.-‘.' The (lt:‘1-'(?lOptm.’ttt‘ over the past two tlecatles oft:-tolecttlat‘ methods for ntat-ttpttlttttott
`ofRN/I anti DNA has ttjFot'tletl ntoleettlar 1-‘irologeits the ability to study 1-'t't'ttl genomes in tlettttl
`that has heretofore not been pos's'ible. There are tmttty tnolecttlar tecltttt'qne.s now ttvatlttble for
`typing and sttlJt_vptng of vtrttses. The artttlable methods tttelt.tde restrt'ett'on fiagtnent length
`pttl_1-'rttot;tJhts'nt
`ttrtttlvsfs'_. Sottthertt blot ttttttlv.9t.9,
`r}'llg()ttt.t('lt.’()llCl{’ fingetprtttt analysts, reverse
`.lt_}-'bt'l(llZttflUtT. DNA enzyme ltt1t?tttt10£'t.s‘.§‘tt_‘,-'. RNase protection analysis. st'ngle-stratttl cottforttttt-
`tron polymotplnstn tttIttt'ysts_.
`ltL’ie‘t‘0(lttp.le.1‘ t?t(J.l)lllt’_';-’ assay, ttttcleothle S(.’qtttE’m'lttg, atttl genome
`segment length pol}-'morpht‘snt attat}-'st's. The methods ltttve t'ertat'tt ttdvantages and a'tstt(lvan—
`tages wt'tt't.'h .S‘lt0ttl(l he eottst'dered in their application to speetfi(.' 1-'trt.tses orfor .s'pec‘t"fit.‘ ptttposes.
`These tec'ltnt'qaes are ltlwly to beconte more widely used in the fittttre fot'epttlerntologt't‘ sttta't'es
`tmrl for lti1’t‘.'u‘flg(tll()t”tS into the pttfl10plt}-‘Sl0l(tg,{1‘ of ‘v‘lt'It.S' tttfet.-tit)n.s.
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`Infectious Coryza: Overview of
`Options.
`P. J. Blackall .
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`the Disease and New Diagnostic
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`627-632
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`Sttmmat}-‘I htfectt'ons cotyztt is t: well—ret‘ogttt'zetl and eomntonly eneottntet'etl upper t‘B_\'plt‘t’tt‘0-"}'
`tract tlt‘sease of eht'ekens that is caused by the bttctertttnt Httemophthts paragttlltttartttn. The
`occurrence of reeettt otttbrealcs in North ./lntetfett has t.’l'lipl’ItL\'l2€(l
`that the thsease can he
`.s'igttt{tettttt in meat eltt‘el(etts as well as layer ehiclcens. la tleveloptng eotttttries.
`('()t}-‘Z£1'
`ts
`eommot'tly cotttplieated by the presence ofa range of other infecttons, resnltt'ng in severe thsease
`tttttl st'gttt'j‘icttnt ecottotnie losses. Unusual fornts of the tltsease, t'nvolvt'ng at'thrttts and septice-
`ntt'a, again assoetatetl with the presence of other pathogens. ha we been found in Soutlt America.
`Nwly teeogntzed bacteria sttclt as Ot‘ttltl‘t0.l)(tCtt’t‘l£tt?‘.'
`t'ltltt()ft‘fl'Clt€Ctl(.’ antl phencttypta variant
`forms of both H. pat‘agalltnat'tttn and dose relatt'ves (1=at'lattt in that they no longer require
`I/-factorfor growth tn vttro} have t'ttcreasea’ the tltflicttlty assot'iatea,' with (lt‘ttgt1t).$‘lttg the tlis'ea.se.
`There have .-‘Jeett sttggestt'ott.s‘ in both Sotttlt /it"tt(.’t'l(.'{t‘ and South /lfrl{'£t that new serovars or
`serovar vttttttttt.s'_. assoet'ated wtth ttnnsttal cltntcttl ntatttfestatton.s' and t.-attst'ttg vat:et'rte fitthtres.
`are etnemtng. Definttit-'e evttlentre to confirm or deny the role of these "1=at'tants" tn vatrcttte
`fattttres is cttrrently not ttvtttlable. A new DNA-hasetl cltttgnostte tecltttiqtte. t'n1:ol1ttng PCR. has
`been reeentl),t a'escrtlJecl and will greatly assist in the tltttgttosts t)ft'ttfec'ttotts cot}-'za.
`
`Molecular Typing of Borrelia burgdotjferi Sensu Lato: Taxonomic,
`Epidemiological, and Clinical
`Implications.
`Guiqing Wang,
`Alje P. van Dam, Ira Schwartz, and Jacob Dankert .
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`633-653
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`Sttttttttaty.‘ Bort‘eh'a ltttrgdotjferi sensn lato, the sptrochete that eattses httman L}-‘ti-‘It.’ l)()t't‘£’ll0Sl.$‘
`(L8).
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`t1h“J3-85 12.-’99_»"$tl4.tJtl s it
`Copyright -13
`IBM‘). American Society for Nlicrobitiltigy, All Rights Reserved.
`
`limit. p. :'stt|—5|';'
`
`Antifungal Agents: Mode of Action, Mechanisms of Resistance, and
`Correlation of These Mechanisms with Bacterial Resistance
`
`MAI-IMOUD A. (ll-IAt‘v'NOLil\/1"” AMI‘) LOUIS B. RICE"
`
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`
`"no-o......
`
`-noun.................................................. nu-co
`
`.. -o.o..oo.ou-cocoa“...-...
`--co-co-canoe...
`
`.........509
`
`unoouoonoouoooiouhoolou
`". .uonoIoouonnnoouolonuu
`
`............ .31]
`
`uunun.-.o....................................u..u .
`
`..................................... ..50]
`INTRODUCTION
`pnonuams wmi coMi3§ii'ii§&§"}{i§i"r'i'i5iiiicAL Ai5i3'I§EiiiiiXEiEi¥iAt. RESISTANCE.......................-502
`DEFINITION OF RESISTANCE
`........................................
`....
`...................................503
`MECHANISMS OF ACTION AND RESISTANCE
`Antimicrobial Agents Affecting Fungal Ste-rols
`Azole-based antimycotic agents......................
`(i] Mechanism of action .....
`...............................................
`(ii) Mechanisms of resistance to azoles
`-nu.-....................
`Polyenes...............................
`{i} Mechanismof
`(ii) Mechanism of resistance to polyenes.
`u-nae...» ..............................................no.-no
`AIlyIaInines........
`scu-Iuutoto-0000000nnlnlcnnannnanuanpcnncnncnncnncnuculc
`{i) Mechanism of action..................
`{ii} Mechanism of resistance to al|_v|anIines......... .... ..
`Compounds Active against Fungal Cell Walls..............
`Inhibitors of glucan synthesis...............................
`uuouuun...
`[1] Mechanism of aetion.............
`(ii) Mechanism of resistance to
`glucan synthesis inhibitors .......
`....... ..
`Compounds Inhibiting Nucleic Acids.......... .............................................
`-..n.o-.oonoo«...
`5-Fluorocytosine .... ..
`uuuuu0-Iooooocoohoouououau
`{i} Mechanism of action......................
`(ii) l\’Iec|i:inism of resistance to 5-fluerocyfosine'...................................................................
`IS THERE A RELATIONSHIP BETWEEN RESISTANCE DEVELOPMENT AND VIRULENCE?
`PREVENTION AND CONTROL OF ANTIFUNGAI. RESISTANCE ...............................
`CONCLUSION............
`ACKNOVVLEDGM ENTS ..
`
`...........513
`'
`
`.-noouu.................... .. nu...
`
`INTRODUCTION
`
`The past decade has witnessed a significant increase in the
`prevalence of resistance to antibacterial and antifungal agents.
`Resistance to antimicrobial agents has important implications
`for morbidity. mortality and health care costs in US. hospitals.
`as well as in the community. Hence. substantial attention has
`been focused on developing a more detailed understanding of
`the mechanisms of antimicrobial resistance. improved Incthods
`to detect resistance when it occurs, new antimicrobial options
`for the treatment of infections caused by resistant organisms.
`and methods to prevent the emergence and spread of resis-
`tance in the first place. Most of this attention has been devoted
`to the study of antibiotic resistance in bacteria for several
`reasons: (i) bacterial infections are responsible for the bulk of
`c0rninunity—acquiretl and nosocomial infections: (ii) the large
`and expanding number of antibacterial classes offers a more
`diverse range of resistance mechanisms to study; and (iii) the
`ability to move bacterial resistance dctcimittants into standard
`well—charactcrizcd bacterial strains facilitates the detailed
`
`" Corresponding author. Mailing addi'css: Center for Medical M_v—
`cology. Department of Dermatology.
`linivcrsity Hospitals of Cleve-
`land.
`I l ltltl Euclid Ave. Lakeside 5028. Cleveland. OH slriltlfi. Phone:
`(llfi) 844-Sfiiifl. Fax:
`(Elli) ts’-14-l07t’i. E—|nail:
`|VlAG3fTiPO.CWRLl
`.l.i[.)U.
`
`study of molecular mechanisms of resistance in bacterial spe-
`cies.
`
`The study of resistance to antifungal agents has lagged be-
`hind that of antibacterial resistance for several reasons. Per-
`
`haps most importantly. fungal diseases were not recognized as
`important pathogens until relatively recently (2. 148). For ex-
`ample. the annual dcath rate due to candidiasis was steady
`between 1950-and about 1970. Since l9'i'(l, this rate increased
`sigiiifieantly in association with several changes in medical
`practice. including more widespread Lise of therapies that de-
`press the immune system. the frequcnt and often indiscrimi-
`nate use of broad-spectrum antibacterial agents. the common
`use of indwelling intravenous devices. and the advent of
`chronic irnniunosuppressive viral
`infections such as AIDS.
`These developments and the associated increase in fungal in-
`fections (5) intensified the search for new. safer. and more
`cfficaciotis agents to combat serious fungal infections.
`For nearly 30 years. amphotcricin B (Fig. I}. which is known
`to cause significant nephrotoxicity. was the sole drug available
`to control serious fungal infections. The approval of the imi-
`dazolcs and the triazoles in late |98Us and early l‘)0tls were
`major advances in our ability to safely and effectively treat local
`and systemic fungal infections. The high safety profile of trio»
`zoles, in particular fluconazole (Fig. 1). has led to their exten-
`sive use. Flueonazole has been used to treat in excess of 16
`million patients. including over 3-tl[l.(l0U AIDS patients. in the
`
`ms malarial may be prmecled by Copyright law (rule 17 us. code)
`
`hill
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`Cal-lA.NNOUM AND RICE
`
`CLIN. Micnosioi. RE\-.
`
`Amphotericin B
`
`Flueonazole
`
`Terbinafine
`
`Voriconazole
`
`Bchinocandin B
`
`FIG.
`
`1. Structures of representative aritilungal agents.
`
`United States alone since the launch of this drug (l24a]. Con-
`comitant with this widespread use, there have been increasing
`reports of antifungal resistance ([15). The clinical impact of
`antifungal resistance has been recently reviewed (I15). Also.
`three excellent reviews concentrating on various aspects of
`antifungal resistance including clinical implications have been
`published recently (2'?, 86, 153). Therefore. the clinical impact
`of resistance is not covered in this review. Instead. our goal is
`to focus on the molecular mechanisms of antifungal resistance.
`Since mechanisms of antibacterial resistance are characterized
`in considerably more detail than those of antifungal resistance.
`we have chosen to use well-described mechanisms of bacterial
`resistance as a framework for understanding fungal mecha-
`nisms of resistance, insofar as such comparisons can be logi-
`cally applied. In so doing, we hope to make an understanding
`of antifungal resistance mechanisms accessible to those who
`use these agents clinically, as well as those who may wish to
`study them in the future.
`
`PROBLEMS WITH COMPARING ANTIFUNGAL AND
`ANTIBACTERIAL RESISTANCE
`
`Although it is our premise that a comparison between mech-
`anisms of resistance to antifungals and antibacterials is a useful
`way of developing a perspective on antimicrobial resistance in
`the two kingdoms, the comparison is necessarily limited by
`several factors. First, the Structures of fungi and bacteria differ
`in very significant ways (such as the diploid nature of most
`fungi and the longer generation time of fungi compared to
`bacteria}, and the available antibacterial and antifungal agents
`target structures and functions most relevant to the organisms
`
`to be inhibited. For example. many antibacterial agents inhibit
`steps important for the formation of pcptidoglycan. the essen-
`tial component of the bacterial cell wall.
`In contrast, most
`antifungal compounds target either the formation or the func-
`tion of ergosterol, an important component of the fungal cell
`membrane. Nevertheless.
`there are important parallels be-
`tween the mechanisms by which fungi develop resistance to
`ergosterol biosynthesis inhibitors and bacteria develop resis-
`tance to anti-cell wall agents. Regarding other types of bacte-
`rial resistance, comparisons are limited by the fact that anti-
`fungal analogues of many classes of antibacterial agents
`{protein synthesis inhibitors such as aminoglycosides. macro-
`lidcs, and tetracyclines; topoisomerase inhibitors such as fluo-
`roquinoloncs; and metabolic pathway inhibitors such
`trimethoprim-sulfarnethoxazolc) do not exist. Conversely, an-
`tifungal nucleoside analogues such as 5-fluorocytosine {SFC)
`have no counterparts among clinically available antibacterial
`agents ("although they are represented among the antiviral
`compounds). As such, the capacity for fungi to develop ribo-
`sornal resistance or topoisomerase mutations is unknown. as is
`the capacity for bacteria to develop resistance to nucleosidc
`analogues.
`Interestingly,
`the antibacterial RNA polymerase
`inhibitor rifampin, which demonstrates no intrinsic activity
`against fungi. appears quite active against several fungal spe-
`cies when uscd in combination with amphotcricin B (8). This
`synergistic activity has been attributed to increased uptake of
`the rifampin into the fungal cell resulting from the action of
`ampbotericin B on the fungal membrane. Similar synergism
`has been demonstrated between anipliotcricin l3 and SFC by
`Polak cl
`211. {I09}, using murine models of candidiasis. The
`mechanism for this synergism has been postulated by some
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`VoI_. 12. I999
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`ANTIFLJNUAI. ACr}'iN'I‘S
`
`503
`
`investigators to be intproved uptake of the SFC as a result of
`ntembraiie disorganization due to amphotericin B—ergostcroi
`inteI'action (87). This synergistic effect resembles the postu-
`lated mechanism of bactericidal synergism between cell wall-
`activc agents and aminoglycosides against cntcrococci,
`in
`which increased intracellular concent1'ations of streptomycin
`are detectable when streptomycin is combined with penicillin
`in vitro against EtI.l'c‘i'(J(I0(’E?.tt.';' fnecniis (9l}.
`in contrast to the
`notion that ampholericin B improves the uptake of SFC. data
`obtained by Beggs et al. (7) suggest that these two agents act
`sequentially and not in combination against Cnitdidrt rtt'bit'aus
`to affect synergy.
`The second limitation to the comparison between antifungal
`and antibacterial resistance mechanisms is that some general
`classes of resistance mechanisms have not yet been identified
`in fungi. Resistance to antibacterial agents results from mod-
`ification of the antibiotic. modification of the antimicrobial
`
`target, reduced access to the target. or some combination of
`these mechanisms. Antibiotic modification is arguably the most
`important mechanism of resistance to the B-lactam ([3—lacta—
`mases) and aminoglyeoside (arninoglycoside-modifying en-
`zymes) classes of antibacterials. In contrast, although there has
`been a single, unconfirmed report of degradation of nystatin by
`dermatophytic fungi (13), there are no data to suggest
`that
`antibiotic modification is an important mechanism of antitan-
`gal resistance. On the other hand, accumulating evidence sug-
`gests that both target alterations and reduced access to targets
`[sometimes in combination} are important mechanisms of re-
`sistance to antifungal agents. These mechanisms have impor-
`tant parallels in antibacterial resistance.
`The third limitation to the comparison is that our knowledge
`of genetic exchange mechanisms in bacteria is far tnorc ad-
`vanced than our knowledge of exchange mechanisms,
`if they
`exist, in fungi. Bacteria employ an extensive repertoire of plas-
`mids,
`transposons, and bacteriophages to facilitate the ex-
`change of resistance and virulence determinants among and
`between species. As a result. the opportunity for rapid emer-
`gcnce of high-level resistance and the potential for emergence
`and dissemination of resistance even in the absence of diI‘cct
`
`selection by specific antimicrobial pressure abound. Con-
`versely, antifungal resistance described to date generally in-
`volves the emergence of naturally resistant species (as in the
`increasing importance of Chrtdida .f(I'tt.5't.’f in areas of extensive
`use in certain medical centers) or the progressive, stepwise
`alterations of cellular structures or functions to avoid the ac-
`
`tivity of an antifungal agent to which there has been extensive
`exposure.
`The final impor