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Insights Into Macrotetrolide Drug Spectrum, Potency and Mode of Action

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Insights Into Macrotetrolide Drug Spectrum, Potency and Mode of Action Medical Mycology April 2013, 51, 280–289 Identifi cation of antifungal natural products via Saccharomyces cerevisiae bioassay: insights into macrotetrolide drug spectrum, potency and mode of action BRAD TEBBETS * † , ZHIGUO YU § , DOUGLAS STEWART * , LI-XING ZHAO ^, YI JIANG ^, LI-HUA XU ^, DAVID ANDES ‡ , BEN SHEN § # & BRUCE KLEIN * † ‡ Departments of * Pediatrics , ‡ Internal Medicine, and † Medical Microbiology and Immunology, the University of Wisconsin School of Medicine and Public Health, Madison, WI, Departments of § Chemistry and # Molecular Therapeutics, The Scripps Research Institute , Jupiter , Florida , USA , and ^ Yunnan Institute of Microbiology, Yunnan University, Kunming , Yunnan , China Since current antifungal drugs have not kept pace with the escalating medical demands of fungal infections, new, effective medications are required. However, antifungal drug discovery is hindered by the evolutionary similarity of mammalian and fungal cells, which results in fungal drug targets having human homologs and drug non-selectivity. The group III hybrid histidine kinases (HHKs) are an attractive drug target since they are conserved in fungi and absent in mammals. We used a Saccharomyces cerevisiae reporter strain that conditionally expresses HHK to establish a high-throughput bioassay to screen microbial extracts natural products for antifungals. We identifi ed macrotetrolides, a group of related ionophores thought to exhibit restricted antifungal activity. In addition to confi rming the use of this bioassay for the discovery of antifungal natural products, we demonstrated broader, more potent fungistatic activity of the macrotetrolides against multiple Candida spp., Cryptococcus spp., and Candida albicans in biofi lms. Macrotetrolides were also active in an animal model of C. albicans biofi lm, but were found to have inconsist- For personal use only. ent activity against fl uconazole-resistant C. albicans , with most isolates resistant to this natural product. The macrotetrolides do not directly target HHKs, but their selective activity against S. cerevisiae grown in galactose (regardless of Drk1 expression) revealed potential new insight into the role of ion transport in the mode of action of these promis- ing antifungal compounds. Thus, this simple, high-throughput bioassay permitted us to screen microbial extracts, identify natural products as antifungal drugs, and expand our understanding of the activity of macrotetrolides. Keywords Fungi , reporter , natural products , drug discovery , macrotetrolide Med Mycol Downloaded from informahealthcare.com by University Of Wisconsin Madison on 08/07/13 Introduction contributing to this trend include the growing number of individuals with compromised immune systems, the The need for novel antifungal drugs has been escalating complexity of medical procedures that render patients over the past 20 years. It is conservatively estimated vulnerable, and the advancing age of our population [1]. that systemic fungal infections have increased over Current antifungal drugs are insuffi cient due to the lim- 200% between 1979 and 2000 [1]. The major factors ited selection of medications, their adverse side-effects, and the emergence of resistance to them by fungal patho- Received 20 February 2012 ; Received in fi nal form 12 June 2012; gens. A recent study reported that 17% of clinical iso- Accepted 8 July 2012. lates of Candida albicans had increased resistance to Correspondence: Bruce Klein, University of Wisconsin-Madison, fl uconazole, a current frontline drug [2]. Therefore, novel Microbial Sciences Building, 1550 Linden Drive, Madison, WI, 53706, USA. Tel.: ϩ 1 608 263 9217; Fax: ϩ 1 608 262 8418; E-mail: bsklein@ drugs are needed to meet the increasing demand for wisc.edu fungal infections. © 2013 ISHAM DOI: 10.3109/13693786.2012.710917 Antifungal natural products via S. cerevisiae bioassay 281 Natural products remain a great source of potential anti- Table 1 Fungal strains used in this study. fungal drugs as evidenced by the fact that both polyenes Organism Notes Reference/source and echinocandins were derived from natural products of microbial origin [3,4]. However, a major drawback in the Saccharomyces cerevisiae W303-1A Parental; ATCC ATCC discovery of such drugs is the diffi culty in identifying and 208352 purifying a compound from a complex extract of a natural Hik1 Expressing Hik1 under galactose Motoyama et al. product. In our ongoing effort to search for new and bio- promoter 2005 [18] logically active natural products produced by actinomy- Drk1 Expressing Drk1 under galactose This study promoter cetes in unexplored and underexplored ecological niches Candida albicans [5 – 9], we assessed in this investigation the feasibility of a 412 Clinical isolate ATCC high-throughput bioassay to screen microbial extracts 1002 Clinical isolate Andes et al. 2006 for antifungal natural products. We took advantage of a [37] 2 – 76 Clinical isolate Andes et al. 2006 Saccharomyces cerevisiae yeast reporter strain that heter- [37] ologously expresses a group IIII hybrid histidine kinase SC5314 Clinical isolate ATCC (HHK) to screen microbial extracts for antifungal activity. C48 Fluconazole-resistant Sanglard et al. Group III HHKs are sensor kinases that regulate sporula- clinical isolate 1995 [38] tion, virulence factors, and morphogenesis in numerous 2823 Fluconazole-resistant Andes et al. 2006 clinical isolate [37] human fungal pathogens including Aspergillus fumigatus , FH5 Fluconazole-resistant Andes et al. 2006 C. albicans , Cryptococcus neoformans , and Blastomyces clinical isolate [37] dermatitidis [10 – 13]. Conservation of HHKs throughout 2307 Fluconazole-resistant Andes et al. 2006 the fungal kingdom, together with their absence in clinical isolate [37] 12 – 99 Fluconazole-resistant Andes et al. 2006 mammals, makes them an attractive drug target. clinical isolate [37] Using this high-throughput reporter-cell bioassay, we 2168 Fluconazole-resistant This study successfully identifi ed antifungal activities in products clinical isolate from a crude microbial extract. Dereplication and struc- Candida glabrata 1906 Clinical isolate This study tural elucidation revealed that the antifungal activities 1907 Clinical isolate This study resulted from the macrotetrolides, i.e., nonactin, monactin, 1 – 215-8377 Clinical isolate This study dinactin, and trinactin, a family of ionphores previously 1 – 218-8640 Clinical isolate This study thought to have only restricted antifungal action [14]. In 3 – 218-8073 Clinical isolate This study Candida krusei addition to demonstrating the application of this bioassay, 1685 Clinical isolate This study For personal use only. we uncovered that the macrotetrolides had broader, more 3459 Clinical isolate This study potent activity against human fungal pathogens than previ- 3 – 219-8544 Clinical isolate This study Candida lusitaniae ously appreciated. They were fungistatic against C. albicans , 556 Clinical isolate This study active against C. neoformans and C. gatti and fl uconazole- 3595 Clinical isolate This study resistant strains of C. krusei , as well as being effective Cryptococcus neoformans in vitro and in vivo with respect to Candida albicans var . grubii H99 Serotype A ATCC biofi lms, a major source of life-threatening bloodstream Cryptococcus gattii infections. However, the majority of fl uconazole-resistant 1266 Clinical isolate Personal C. albicans strains were resistant to the macrotretrolides. communication * While they do not directly target HHKs, macrotetrolides 1269 Clinical isolate Personal S. cerevisiae communication * selective activity against parental grown in Aspergillus fumigatus Med Mycol Downloaded from informahealthcare.com by University Of Wisconsin Madison on 08/07/13 galactose implies that potassium ion transport may have a PI 17 Clinical isolate This study pivotal role in the mode of action of this promising class PI 18 Clinical isolate This study of antifungal natural products. PI 19 Clinical isolate This study * Strain kindly provided by Dee Carter from the University of Sydney, Australia. Materials and methods Fungal strain and growth conditions under the regulation of the GAL1 galactose promoter (it was kindly provided by Takayuki Motoyama from RIKEN The collection of fungal isolates used in this study is listed Wako, Japan) and was grown at 30 ° C. Yeast peptone dex- in Table 1, the majority of which represent human patient trose (YPD) was used as a complete medium, and yeast isolates. The S. cerevisiae reporter strain heterologously synthetic complete (SC) served as a minimal medium [15]. expresses Hik1, a group III HHK from Magnaporthe grisea , Candida spp. cultures were maintained on YPD at 30 ° C, © 2013 ISHAM, Medical Mycology, 51, 280–289 282 Tebbets B. et al . while Cryptococcus spp. and Aspergillus spp. isolates were High-throughput screen of microbial extracts grown on YPD at 37 ° C. The microbial extracts were screened in two steps. First, Unless otherwise noted, supplies and reagents were the S. cerevisiae reporter strain, with Hik1 under the con- purchased from Sigma-Aldrich or Fisher Scientifi c. Com- trol of a galactose-inducible promoter, was added to 96-well mercial antifungals were obtained from the pharmacy of plates with SC medium lacking uracil and containing the University of Wisconsin Hospital and Clinics, Madison, galactose at 0.1 OD /well. The microbial extracts were WI, USA. 600nm added to wells, with the medium and fl udioxonil serving as negative and positive controls, respectively.
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