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View U.S. Patent Application Publication No. US-2019-0300926 In 1111111111111111 IIIIII IIIII 111111111111111 1111111111 11111 1111111111 11111 1111111111 11111111 US 20190300926Al c19) United States c12) Patent Application Publication c10) Pub. No.: US 2019/0300926 Al Hull et al. (43) Pub. Date: Oct. 3, 2019 (54) METHOD TO SCREEN COMPOUNDS FOR A61K 311137 (2006.01) ANTIFUNGAL ACTIVITY AND A61P31/10 (2006.01) PHARMACEUTICAL COMPOSITIONS AND (52) U.S. Cl. METHODS TO TREAT FUNGAL DISEASES CPC ................. C12Q 1118 (2013.01); C12Q 1166 BY INHIBITING SPORE GERMINATION (2013.01); A0lN 41112 (2013.01); A0lN 47140 (2013.01); A0lN 37144 (2013.01); A61P (71) Applicant: WISCONSIN ALUMNI RESEARCH 31/10 (2018.01); A61K 311145 (2013.01); FOUNDATION, Madison, WI (US) A61K 311155 (2013.01); A61K 31124 (2013.01); A61K 311137 (2013.01); A0lN (72) Inventors: Christina Marie Hull, Middleton, WI 33/10 (2013.01) (US); Mingwei Huang, Madison, WI (US); Sebastien Claude Ortiz, (57) ABSTRACT Madison, WI (US) A method of testing compounds for activity to inhibit (21) Appl. No.: 16/369,939 germination of spores. The method includes the steps of providing bacterial, fungal, or plant spores transformed to (22) Filed: Mar. 29, 2019 contain and express a detectable marker, wherein the marker when expressed, is operationally linked to a spore-specific Related U.S. Application Data or yeast-specific protein, in a medium and under environ­ (60) Provisional application No. 62/649,802, filed on Mar. mental conditions in which the spores will germinate, and 29, 2018. measuring a first signal output generated by the marker prior to the spores initiating germination; contacting the spores of Publication Classification step (a) with a compound whose activity to inhibit germi­ nation of spores is to be measured; incubating the spores of (51) Int. Cl. step (b) under environmental conditions and for a time C12Q 1118 (2006.01) wherein spores not treated with the compound will germi­ C12Q 1166 (2006.01) nate; and determining extent of germination of the spores by A0lN 41112 (2006.01) measuring a second signal output generated by the marker, A0lN 47140 (2006.01) wherein a difference between the first signal output and the A0lN 37144 (2006.01) second signal output is proportional to the extent of germi­ A0lN 33/10 (2006.01) nation of the spores. Also described are compositions of A61K 311145 (2006.01) matter for inhibiting spore germination in vitro and in vivo. A61K 311155 (2006.01) A61K 31124 (2006.01) Specification includes a Sequence Listing. Patent Application Publication Oct. 3, 2019 Sheet 1 of 13 US 2019/0300926 Al b 100 90 80 70 60 50 40 so 20 • $pcore-s {K.N99a: xKN99<t) 10 ·. o ·V~.a$t {1: 1, KN99a and KNOOq} O+----r------~---------<-:rr---- h V 1{J 20 30 Days po$t infecfion FIG.1 Patent Application Publication Oct. 3, 2019 Sheet 2 of 13 US 2019/0300926 Al <( ,:Q N N C, C, u. u. Patent Application Publication Oct. 3, 2019 Sheet 3 of 13 US 2019/0300926 Al Ptot:ein-N~:t:KiLrnc:if:erase {NL; FlJsion g,ene t:i:mstmtt .,,,fl°$::::~&~"~ e Sa:rna! l development ·. •· Nano--·Gh 1 Ass.wt ·.· l .::::::,.::::::: .ori······················ to:h····················22h············* 0 :.;:;:1: «l<:.,,.~ sssssss<'(c- ·o·.,. q,,...,_. ~· ""'"'~· o·,est,~.'.~c.i FIG. 3A Patent Application Publication Oct. 3, 2019 Sheet 4 of 13 US 2019/0300926 Al . C, u.. Patent Application Publication Oct. 3, 2019 Sheet 5 of 13 US 2019/0300926 Al FIG.3C Patent Application Publication Oct. 3, 2019 Sheet 6 of 13 US 2019/0300926 Al . C> u.. Patent Application Publication Oct. 3, 2019 Sheet 7 of 13 US 2019/0300926 Al ·r:7,:;::jtJ ;:,~❖:f.'(❖ :.--1":« <:-.-.:.-·'.l'w,-:.~,...,_..,...._.:·::-;.:: cm:~: Ni;0.:;-:_~-:§.:XS5'\!­ J/ t tt1~i~:~:1 ; ~:•,:::(,:'.l:~ :r.:::~%:~: .:.:.1{:!'.!:,:,x•~•::,x-:.: ❖ i ~Y-8:~.~~~~~~ -?~:~~~:- {~}~ -::::.:!:~:~;....~:-j:5 :·.=:-.:.:-! ❖:' ?*:P..-.!;:;&,":!~;: ~{) ~-:.., :.~.:-:.-(-.x,-.;,·.:-,y,,.;,. '":<1-!".ff_.: ::~"!... ;;u&.1~;~~;~ .s-:;:~~:;:y i >;fr:.: ❖ r.:-~-r:.x-::.:t -~:;, C;;i:-0.;;::~9.i ~:;::. ~>~-::r«.Z.:.:.:~ :r,:-:r::'.7.❖r!, FIG.4 Patent Application Publication Oct. 3, 2019 Sheet 8 of 13 US 2019/0300926 Al r.;d;. C) ' -LL. 4Ji?~ Ct' <( Ln C) LL. f .. C·. Patent Application Publication Oct. 3, 2019 Sheet 9 of 13 US 2019/0300926 Al {,:':fx':{.t rnlto ,fw,1; Bl,gat:ithrn <JUilr.tirBtt?:.i si.ze,':Shape of hundrnd~ t.lf cell$ phOtos cf genninatin;;l sporn,s ln microdevice FIG.6 Patent Application Publication Oct. 3, 2019 Sheet 10 of 13 US 2019/0300926 Al A, (lh '.W -~-==~~~ ::::::::: =::-::~:-;%§.:?.::. - :::~:<~-=::..; Patent Application Publication Oct. 3, 2019 Sheet 11 of 13 US 2019/0300926 Al PBS SD 0 :;:; [!: .....u QJ 0. V, <( 0 5 10 15 20 25 0 5 10 15 20 25 Area µm2 Area µm2 0 ·.;::; Fluconazole [!: ti QJ 0. V, <( 0 5 10 15 20 25 Area µm2 FIG. 7B Patent Application Publication Oct. 3, 2019 Sheet 12 of 13 US 2019/0300926 Al ~* 1i)l r t······················;* ,·······························----····; I 1· ,,.I ! [ ,..! ................•• ... 1{P ,.... •.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•·'"··········································'············································ '~-~ntrij 4 1l"'fl/~gir.fay f:°¼ff:i;~r::~id:i~-~~ Tmatrnent Tre~!ment FIG. SA FIG.SB Patent Application Publication Oct. 3, 2019 Sheet 13 of 13 US 2019/0300926 Al . '. •• u 4 m?;;;t'\ij/d~f. P~,nbmd:ine Prophiyktctic rreatrnent FIG. 9 US 2019/0300926 Al Oct. 3, 2019 1 METHOD TO SCREEN COMPOUNDS FOR [0006] Spore-producing fungi commonly generate spores ANTIFUNGAL ACTIVITY AND with thick, protective coats and robust stress resistance. PHARMACEUTICAL COMPOSITIONS AND Spores respond to different environmental signals to initiate METHODS TO TREAT FUNGAL DISEASES germination, depending on their adapted niches. For BY INHIBITING SPORE GERMINATION example, spores of S. cerevisiae germinate readily in response to the presence of a fermentable carbon source. In CROSS-REFERENCE TO RELATED contrast, spores of Talaromyces macrosporus require nutri­ APPLICATIONS ents and a rigorous external trigger of very high temperature or pressure. These triggers generally result in responses such [0001] Priority is hereby claimed to provisional applica­ as water uptake, cell wall remodeling, and activation of tion Ser. No. 62/649,802, filed Mar. 29, 2018, which is nutrient metabolism and protein synthesis, leading to active incorporated herein by reference. fungal growth. [0007] The transition from dormant particle to actively FEDERAL FUNDING STATEMENT growing cell is particularly important because fungal sur­ [0002] This invention was made with govermnent support vival cannot occur in the absence of the ability to germinate under AI089370 awarded by the National Institutes of when (and only when) appropriate for vegetative growth. Health. The govermnent has certain rights in the invention. Environmental fungi are well adapted to their niches, and interestingly, these adaptations have led to a handful of fungi BACKGROUND with the ability to cause life-threatening diseases in humans. Histoplasma capsulatum, Blastomyces dermatitidis, Asper­ [0003] Spores are an essential cell type required for long­ gillus fumigatus, Coccidioides immitis, Sporothrix schenkii, term survival across diverse organisms and are a hallmark of Penicillium marneffei, and Cryptococcus neoformans are the fungal reproduction, persistence, and dispersal. Among most common environmental fungi that can cause disease in human fungal pathogens, spores are presumed infectious humans. The general route of infection is by inhaling cells particles, but relatively little is known about this robust cell from environmental sources. Spores (sexual or asexual, type. Sporulation enables a relative quiescence-a type of depending on the fungus) are the most likely infectious hibernation-that contributes to the survival of fungi. How­ particles for all of these pathogens; however, very little is ever, sporulation also requires a transition back into a known about their basic spore biology, making the devel­ vegetative form so that the fungi can replicate-i.e., germi­ opment of disease prevention and treatment strategies chal­ nation. Germination, despite its central importance in fungal lenging. reproduction and pathology in plants and animals, is not well [0008] Among human fungal pathogens, the most com­ understood. mon cause of fatal fungal disease (and a well-developed [0004] Spores are a particularly successful cell type used model for study) is Cryptococcus neoformans, a primarily by many microorganisms, including bacteria, fungi, and opportunistic pathogenic yeast that causes meningoencepha­ protozoa to survive unsuitable growth conditions and/or to litis. People with AIDS are particularly susceptible, and disperse to new environments. Among eukaryotes, some of there are an over 200,000 cases and nearly as many deaths the most environmentally resistant spores are those of fungi, annually worldwide from cryptococcosis. Rajasingjam R, and much of our current understanding of spores comes Smith RM, Park B J, Jarvis J M, Govender N, Chiller TM, from studies in model fungi such as Saccharomyces cerevi­ Denning D W, Loyse A, Boulware D R (2017) "Global siae and Aspergillus nidulans. There are two general cat­ burden of disease of HIV-associated cryptococcal meningi­ egories of fungal spores-sexual and asexual, and both tis: and updated analysis" Lancet Infectious Disease 17: forms occur across diverse fungal species via myriad devel­ 873-881 (pmid:2848341). C. neoformans is ubiquitous in opmental strategies. For example, in the budding yeast S. the environment, and inhalation of aerosolized spores
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