Cationic amphiphilic drugs are potent inhibitors of yeast sporulation.
Meiosis is a highly regulated developmental process that occurs in all eukaryotes that engage in sexual reproduction. Previous epidemiological work shows that male and female infertility is rising and environmental factors, including pollutants such as organic solvents, are thought to play a role in this phenomenon. To better understand how organic compounds interfere with meiotic development, the model organism Saccharomyces cerevisiae was exposed to 446 bioactive molecules while undergoing meiotic development, and sporulation efficiency was quantified employing two different high-throughput assays. 12 chemicals were identified that strongly inhibited spore formation but did not interfere with vegetative growth. Many of these chemicals are known to bind to monoamine-receptors in higher eukaryotes and are cationic amphiphilic drugs. A detailed analysis of one of these drugs, tripelennamine, revealed that it induces sporulation-specific cytotoxicity and a strong inhibition of meiotic M phase. The drug, however, only mildly interfered with pre-meiotic DNA synthesis and the early meiotic transcriptional program. Chemical-genomic screening identified genes involved in autophagy as hypersensitive to tripelennamine. In addition, we found that growing and sporulating yeast cells heterozygous for the aminophospholipid translocase, NEO1, are haploinsufficient in the presence of the drug.
Stanford Genome Technology Center, Stanford University, Palo Alto, California, United States of America. ulrich.schlecht@stanford.edu
Ulrich
U
Schlecht
Robert P
RP
St Onge
Thomas
T
Walther
Jean-Marie
JM
François
Ronald W
RW
Davis
D000935:Antifungal Agents / Q000494:pharmacology; D001343:Autophagy; D002412:Cations / Q000737:chemistry*; D004247:DNA / Q000096:biosynthesis; D015195:Drug Design; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D023281:Genomics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008540:Meiosis; D055432:Metabolomics / Q000379:methods; D008957:Models, Genetic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D013172:Spores, Fungal / Q000378:metabolism / Q000502:physiology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic; D014309:Tripelennamine / Q000494:pharmacology
D000935:Antifungal Agents; D002412:Cations; D013501:Surface-Active Agents; D049452:Green Fluorescent Proteins; D014309:Tripelennamine; D004247:DNA