[논문]Systematic Target Screening Revealed That Tif302 Could Be an Off-Target of the Antifungal Terbinafine in Fission Yeast

Lee, Sol; Nam, Miyoung; Lee, Ah-Reum; Lee, Jaewoong; Woo, Jihye; Kang, Nam Sook; Balupuri, Anand; Lee, Minho; Kim, Seon-Young; Ro, Hyunju; Choi, Youn-Woong; Kim, Dong-Uk; Hoe, Kwang-Lae

doi:10.4062/biomolther.2020.166

[국내논문] Systematic Target Screening Revealed That Tif302 Could Be an Off-Target of the Antifungal Terbinafine in Fission Yeast 원문보기

Biomolecules & therapeutics, v.29 no.2, 2021년, pp.234 - 247

Lee, Sol (Department of New Drug Development, Chungnam National University) , Nam, Miyoung (Department of New Drug Development, Chungnam National University) , Lee, Ah-Reum (Department of New Drug Development, Chungnam National University) , Lee, Jaewoong (Department of New Drug Development, Chungnam National University) , Woo, Jihye (Department of New Drug Development, Chungnam National University) , Kang, Nam Sook (Department of New Drug Development, Chungnam National University) , Balupuri, Anand (Department of New Drug Development, Chungnam National University) , Lee, Minho (Department of Life Science, Dongguk University-Seoul) , Kim, Seon-Young (Personalized Genomic Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) , Ro, Hyunju (Department of Biological Science, College of Bioscience & Biotechnology, Chungnam National University) , Choi, Youn-Woong (Korea United Pharm. Inc.) , Kim, Dong-Uk (Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB)) , Hoe, Kwang-Lae (Department of New Drug Development, Chungnam National University)

Abstract ▼ AI-Helper

We used a heterozygous gene deletion library of fission yeasts comprising all essential and non-essential genes for a microarray screening of target genes of the antifungal terbinafine, which inhibits ergosterol synthesis via the Erg1 enzyme. We identified 14 heterozygous strains corresponding to 10 non-essential [7 ribosomal-protein (RP) coding genes, spt7, spt20, and elp2] and 4 essential genes (tif302, rpl2501, rpl31, and erg1). Expectedly, their erg1 mRNA and protein levels had decreased compared to the control strain SP286. When we studied the action mechanism of the non-essential target genes using cognate haploid deletion strains, knockout of SAGA-subunit genes caused a down-regulation in erg1 transcription compared to the control strain ED668. However, knockout of RP genes conferred no susceptibility to ergosterol-targeting antifungals. Surprisingly, the RP genes participated in the erg1 transcription as components of repressor complexes as observed in a comparison analysis of the experimental ratio of erg1 mRNA. To understand the action mechanism of the interaction between the drug and the novel essential target genes, we performed isobologram assays with terbinafine and econazole (or cycloheximide). Terbinafine susceptibility of the tif302 heterozygous strain was attributed to both decreased erg1 mRNA levels and inhibition of translation. Moreover, Tif302 was required for efficacy of both terbinafine and cycloheximide. Based on a molecular modeling analysis, terbinafine could directly bind to Tif302 in yeasts, suggesting Tif302 as a potential off-target of terbinafine. In conclusion, this genome-wide screening system can be harnessed for the identification and characterization of target genes under any condition of interest.

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표/그림 (8)

표 Table 1. List of the top 14 terbinafine targets
그림 Fig. 1. Functional analyses of the 14 heterozygous TRB target strains. (A) The erg1 mRNA levels without TRB treatment were measured by using RT-PCR and normalized over act1. (B) The squalene levels after TRB treatment were determined by using HPLC. The bars were filled with various brightness of black color to represent the GO term and dispensability of each heterozygous deletion strain, as indicated on the insets. n=3; *p<0.05, **p<0.01, or ***p25-fold), moderate (5-25-fold), mild (<5-fold), and not susceptible; terbinafine (TRB), tolnaftate (TFT), econazole (ECZ), miconazole (MCZ), diethylstilbesterol (DES), cycloheximide (CHX), and methyl methanesulfonate (MMS).
그림 Fig. 2. Functional analyses of the 9 haploid TRB target strains. (A) For loss-of-function analysis, the haploid deletion strains were retrieved from their cognate heterozygous TRB target strains when their relevant genes were non-essential. Their relative susceptibility in response to the indicated drugs or toxic chemicals compared with ED668 was assessed by using spotting assays, and visualized as a pattern map. The haploid deletion strains of 7 random genes were used as controls. The extent of relative susceptibility is represented as indicated on the inset. Severe (>25-fold), moderate (5-25-fold), mild (<5-fold), and not susceptible; terbinafine (TRB), tolnaftate (TFT), econazole (ECZ), miconazole (MCZ), diethylstilbesterol (DES), cycloheximide (CHX), and methyl methanesulfonate (MMS). (B) The erg1 mRNA levels without TRB treatment were measured by using RT-PCR and normalized over act1. The bars were filled with various brightness of black color to represent the GO term of each haploid deletion strain, as indicated on the insets. n=3; *p<0.05, **p<0.01, or ***p<0.001 vs. ED668.
그림 Fig. 3. The proposed model for the action mechanism of the 7 non-essential RP genes. The 4 test strains harbor the indicated number of RP genes depending on their ploidy and deletion status. Note that RP should serve as components of repressor complexes for erg1 transcription, as speculated by the experimental ratio of their erg1 mRNA levels (on the top box). In turn, the number of repressors (a) is determined by the considering the stoichiometry among components, as indicated. After corrections considering the copy number of erg1 gene (b) and dilution factor due to different cellular volumes (c), the final number of repressors is calculated by the equation of a/b/c (on bottom), which is in a reverse order compared with that of the experimental ratio of erg1 mRNA.
그림 Fig. 4. Drug-drug target interactions of the 4 heterozygous TRB target strains in response to the co-treatment with TRB and ECZ. (A) The isobologram analysis of the heterozygous strains corresponding to the essential genes (erg1, tif302, rpl31, and rpl2501) was performed and their isobologram patterns were compared with that of the SP286 control. The abscissa and ordinate units (solid dots) correspond to the doses of TRB and ECZ. The downward concaves (dotted lines) and the diagonal lines represent the synergistic and additive effects, respectively. n=3; terbinafine (TRB) and econazole (ECZ). (B) Complementation of the tif302 heterozygous strain by ectopic expression of the tif302 or erg1 gene. The tif302 heterozygous strain was transformed with the expression plasmid pREP4X harboring the tif302 (grey bar) or erg1 (dark grey bar) gene. The growth fitness of the transformants was measured in the presence of TRB, and compared with that of the SP286 or tif302 heterozygous strain (Δtif302/tif302) harboring the vehicle (white bar). n=3; *p<0.05 or **p<0.01 vs. SP286;^#p<0.05 or ^##p<0.01 vs. tif302 heterozygote; ^§p<0.01 vs. tif302 heterozygote harboring the ectopic tif302 gene.
그림 Fig. 5. Drug-drug target interactions of the 4 heterozygous TRB target strains in response to the co-treatment with TRB and cycloheximide and a proposed action mechanism based on their isobologram patterns. (A) The isobologram analysis of the heterozygous strains corresponding to the essential genes (erg1, tif302, rpl31, and rpl2501) was performed and their isobologram patterns were compared with that of the SP286 control. The abscissa and ordinate units (solid dots) correspond to the doses of TRB and CHX. The upward convex (dotted lines) and the diagonal lines represent the antagonistic and additive effects, respectively. n=3; terbinafine (TRB) and cycloheximide (CHX). (B) The proposed action mechanism of TRB and CHX. The model was proposed to explain the antagonistic effects of the isobologram pattern. Notably, Tif302 can be inhibited by TRB and its inhibition subsequently affects the protein translation process, which overlaps with the action mechanism of CHX.
그림 Fig. 6. Comparison of binding energy between terbinafine (TRB) and its target proteins including yeast Erg1 and Tif302, and their human orthologs. From the available crystal structures of the human SQLE, human EIF3B, and budding yeast Prt1p proteins, unknown protein structures of interest such as fission yeast Erg1 and Tif302 and budding yeast Erg1p were built via homology modelling. The binding energy between TRB and the indicated proteins was calculated through the generation of 3D affinity grid fields. TRB and residues in binding sites are represented using stick and slender models, respectively. Hydrogen bonds, hydrophobic-, and pi-sigma interactions are indicated as green, pink, and purple dashed lines, respectively (see supplementary material for more details).
그림 Fig. 7. Overview of action mechanisms of all the terbinafine (TRB) target genes screened so far. The action mechanisms of the 14 TRB target genes revealed from the heterozygous library in this study are illustrated along with those of non-essential target genes previously reported (Fang et al., 2012). Notably, Tif302 can serve as a potential secondary off-target of TRB.

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표제어: PCR

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용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

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