we stood at the bedside of a tiny infant in the neonatal intensive care unit .
another member of our infectious disease team had just gotten off the phone with the microbiology lab : a yeast had grown from the blood culture .
when i told the residents ,  he has a one in four chance of dying from this infection ,  they did not believe me . despite antifungal therapy
our patient highlights the urgent need for new , potent antifungal therapies . here in the united states
, our outstanding care of vulnerable populations , such as very low birth weight infants and bone marrow transplant recipients , means that these individuals no longer succumb to their primary diseases but live on with increased susceptibility to opportunistic pathogens , particularly fungi . in resource - limited settings ,
the need for safe , inexpensive , oral antifungal therapies is even more pressing . according to the world health organization
, there are now 35 million individuals living with hiv ; of these , over 70% live in sub - saharan africa , and only half receive antiretroviral therapy ( 1 ) . as a result ,
opportunistic pathogens that are thankfully rare in the developed world are still both common and severe there .
critical among these is the central nervous system pathogen cryptococcus neoformans , a ubiquitous environmental yeast , which causes 1 million cases of meningitis in immunocompromised hosts each year . because the expensive intravenous therapies that comprise the standard of care are unavailable , mortality rates are high , and over half of these patients die .
new antifungal development has been slowed by several challenges , many of which are shared by efforts directed against other eukaryotic pathogens of the developing world , such as the malaria parasite .
these obstacles are in large part scientific ; it is inherently more difficult to identify compounds that selectively harm eukaryotic microbes , since so many essential cellular processes are indeed well conserved from yeasts to humans . in addition , new agents to treat cryptococcal meningitis must cross the blood - brain barrier , a challenge met by only a small minority of existing antimicrobials .
however , the economic challenges to new antifungal development for the developing world are also substantial .
there is little drive to invest significant research and development funds into new pharmaceuticals for resource - limited countries when the expected financial return on investment is negligible .
one strategy to reduce the considerable expense of anti - infective development is the concept of drug repurposing .
investigators screen for new activities present in compounds that are known to be pharmacologically active and , in many cases , are already approved for clinical use .
hits from these screens are , by definition , drug - like molecules that are typically excellent scaffolds for medicinal chemistry optimization , even if they are not immediately suitable for their new purpose . in addition , pharmaceutical companies often have panels of similar compounds from their own development efforts already synthesized and waiting on the shelf , and academic investigators may be able to  piggyback  on those previous research programs .
drug repurposing can be an outstanding starting point for product development and may also illuminate novel biology .
for example , a recent screen for compounds with in vitro activities against the diarrhea pathogen cryptosporidium parvum identified antiparasitic activity in the widely used statin class of cholesterol - lowering drugs , thus revealing an unexpected dependence in this protozoan on host isoprenoid biosynthesis ( 2 ) . however , drug repositioning screens are often far more difficult to interpret biologically , since the molecular mechanisms of action of many agents are obscure .
such was the case for the repurposing screen that identified unexpected antifungal activity in the estrogen receptor antagonist tamoxifen .
while tamoxifen has chemical features that are ideal for a new antifungal treatment  it is orally bioavailable and accumulates in the brain and within lysosomes  the molecular mechanism of its antifungal activity was not clearly defined .
in an extensive and multidisciplinary effort , butts et al . define the mechanisms of action of the estrogen receptor antagonist tamoxifen and related compounds ( the triphenylethylenes ) as new therapies against cryptococcus neoformans ( 3 ) . in this study , the authors report the key early preclinical efficacy studies , which demonstrate the promise of this new class of antifungals .
a major limitation of the currently available oral anticryptococcal agent fluconazole is that this compound arrests the growth of cryptococcus but does not kill the yeast directly .
importantly , the authors demonstrate that the triphenylethylenes not only are fungicidal in combination with fluconazole but also inhibit the intraphagocytic growth of the yeast and already show promise in a mouse model of central nervous system cryptococcal infection .
previous studies on the triphenylethylenes had suggested that tamoxifen and related compounds might interfere with calcium homeostasis ( 46 ) .
this was a promising hypothesis , as the calcium - dependent serine - threonine phosphatase calcineurin is a well - validated target for antifungal development ( reviewed in reference 7 ) .
calcineurin inhibitors , such as the popular immunosuppressants cyclosporine ( csa ) and tacrolimus ( fk506 ) , have potent activities against c.  neoformans , which requires calcineurin for growth at elevated temperatures and therefore mammalian pathogenesis ( 8) . using multiple lines of investigation , butts et al .
establish that the antifungal effects of tamoxifen and its analogs are mediated , at least in part , through direct inhibition of c.  neoformans calmodulin ( cncam1 ) , a calcineurin activator ( fig .  1 ) .
cncam1 protein interacts directly with the triphenylethylenes , which inhibit cncam1-mediated calcineurin activation in vitro .
cellular overexpression of cncam1 decreased sensitivity to this group of compounds , also supporting the finding that cncam1 is a direct target in vivo . consistently with these findings , the triphenylethylenes interfere with cellular functions downstream of calcineurin , which is known to be required for c.  neoformans virulence .
genetic screening also revealed an apparent second , related target , calmodulin - like protein ( cml1 , cnag_05655 ) , whose deletion led to compound resistance .
calmodulin is an activator of the serine - threonine phosphatase calcineurin , which is required for virulence in the pathogenic fungus cryptococcus neoformans .
calcineurin is the target of the commonly used immunosuppressants cyclosporine a ( csa ) and tacrolimus ( fk506 ) , which also inhibit mammalian calcineurin in t cells .
the current study provides a strong foundation for future medicinal chemistry efforts to optimize the triphenylethylene scaffold in developing novel antifungal agents .
preliminary structure - activity relationships among the tamoxifen analogs indicate that potency against the cncam1 target is well correlated with antifungal activity . by starting with a compound class that is orally bioavailable , with intracellular activity and an optimal tissue distribution pattern ,
there is real hope that we may cut the time and cost of drug development and bring forward a new anticryptococcal agent for the developing world .
 abstractnew antifungals are needed , particularly in the developing world , to treat life - threatening fungal infections , such as cryptococcosis . 
 drug repurposing is one strategy to identify new drug - like compounds , but it is often difficult to identify a mechanism of action . here 
 we discuss the outstanding effort by butts et al . 
 to identify calmodulin as an antifungal target of repurposed estrogen receptor antagonists [ a. butts , k. koselny , y. chabrier - rosell , c. p. semighini , y. c. s. brown , et al . 
 , mbio 5(1):e00765 - 13 , 2014 , doi:10.1128/mbio.00765 - 13 ] . 
 the authors show that these compounds bind to and directly inhibit fungal calmodulin and also reduce fungal burden in an animal disease model . 
 these studies thus establish both the key preclinical efficacy and the antifungal mechanism of action , which will allow these compounds to progress toward development of novel antifungal therapies . 
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