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Most existing antibiotics were discovered through screens of environmental microbes, particularly the streptomycetes, for the capacity to prevent the growth of pathogenic bacteria. This "activity-guided screening" method has been largely abandoned because it repeatedly rediscovers those compounds that are highly expressed during laboratory culture. Most of these metabolites have already been biochemically characterized. However, the sequencing of streptomycete genomes has revealed a large number of "cryptic" secondary metabolic genes that are either poorly expressed in the laboratory or that have biological activities that cannot be discovered through standard activity-guided screens. Methods that reveal these uncharacterized compounds, particularly methods that are not biased in favor of the highly expressed metabolites, would provide direct access to a large number of potentially useful biologically active small molecules. To address this need, we have devised a discovery method in which a chemical elicitor called Cl-ARC is used to elevate the expression of cryptic biosynthetic genes. We show that the resulting change in product yield permits the direct discovery of secondary metabolites without requiring knowledge of their biological activity. We used this approach to identify three rare secondary metabolites and find that two of them target eukaryotic cells and not bacterial cells. In parallel, we report the first paired use of cheminformatic inference and chemical genetic epistasis in yeast to identify the target. In this way, we demonstrate that oxohygrolidin, one of the eukaryote-active compounds we identified through activity-independent screening, targets the V1 ATPase in yeast and human cells and secondarily HSP90.

Bacteria in the genus Streptomyces are found ubiquitously in nature and are known for the number and diversity of specialized metabolites they produce, as well as their complex developmental lifecycle. Studies of the viruses that prey on Streptomyces, known as phages, have aided the development of tools for genetic manipulation of these bacteria, as well as contributing to a deeper understanding of Streptomyces and their behaviours in the environment. Here, we present the genomic and biological characterization of twelve Streptomyces phages. Genome analyses reveal that these phages are closely related genetically, while experimental approaches show that they have broad overlapping host ranges, infect early in the Streptomyces lifecycle, and induce secondary metabolite production and sporulation in some Streptomyces species. This work expands the group of characterized Streptomyces phages and improves our understanding of Streptomyces phage-host dynamics. [ABSTRACT FROM AUTHOR]

The motif of the mortal-spectral threshold runs through the practice of Singapore-based artist, Zarina Muhammad. Born Malay-Muslim, she identifies as a queer animist: her body of work is oriented around notions of the interstitial spaces that exist between the living and the otherworldly in Southeast Asian traditions, incorporating elements of ritual, magic, and the supernatural, poised in the discursive space between animist belief and monotheistic orthodoxy. It is the concept of spectrality, as an organizing metaphor, that provides the primary framework within which her installations and moving images are deciphered. Here, the ghostly and incorporeal are as much synonyms for the sphere of the spiritual and paranormal, as they are analogies for the socially other-ed and systematically marginalized, excluded by dominant ideologies and systems. In the context of the heteronormative, technocratic order and orthodox Islamic lifeworld of twenty-first century Singapore, Zarina's intersecting identities as a queer, Malay-Muslim woman are read as apparitions of alterity, haunting the margins of hegemonic structures. The liminal site of the threshold signifies the spectral realms invoked in her work, and ultimately serves to metaphorize broader socio-cultural realities. [ABSTRACT FROM AUTHOR]