Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy

Thiopeptide antibiotics are emerging clinical candidates that exhibit potent antibacterial activity against a variety of intracellular pathogens, including Mycobacterium tuberculosis (Mtb). Many thiopeptides directly inhibit bacterial growth by disrupting protein synthesis. However, recent work has shown that one thiopeptide, thiostrepton (TSR), can also induce autophagy in infected macrophages, which has the potential to be exploited for host-directed therapies against intracellular pathogens, such as Mtb. To better define the therapeutic potential of this class of antibiotics, we studied the host-directed effects of a suite of natural thiopeptides that spans five structurally diverse thiopeptide classes, as well as several analogs. We discovered that thiopeptides as a class induce selective autophagic removal of mitochondria, known as mitophagy. This activity is independent of other biological activities, such as proteasome inhibition or antibiotic activity. We also find that many thiopeptides exhibit potent activity against intracellular Mtb in macrophage infection models. However, the thiopeptide-induced mitophagy occurs outside of pathogen-containing autophagosomes and does not appear to contribute to thiopeptide control of intracellular Mtb. These results expand basic understanding of thiopeptide biology and provide key guidance for the development of new thiopeptide antibiotics and host-directed therapeutics

Slow Resilience: Speculative Fiction in the Capitalocene

Slow Resilience: Speculative Fiction in the Capitalocene argues that authors of contemporary speculative fiction, in writing about Capitalocenic disasters, engage their characters and readers in practices of slow resilience. I develop a theory of slow resilience as a series of survival strategies within and beyond global capitalism, allowing for both utopian critiques of and corrections to that system, and ways of coping within its lived realities. The project considers how speculative fiction novels, essays, treatises, and self-styled documentaries—“what if” narratives—are uniquely suited to grapple with imagining other futures that are based on current conditions, as they border on but do not cross into the improbable or fantastic. Attending to the difficulties of representing slowly evolving, non-spectacular crises like global climate change, Slow Resilience maps a spectrum of narrative and affective responses to such Capitalocenic disasters, from denial, fear, and sublime awe to utopian dreams of communal living, extra-solar travel, and inter-species coexistence. I propose that speculative fiction in the Capitalocene portrays the long, slow, monotonous business of survival under the threat of, and beyond, apocalypse, parodying Romantic ideas of a noble Last Man while also offering up counter-narratives of a Last Woman, who struggles to survive in what I call the Gothic conditions of neoliberal capitalism. Each work of speculative fiction addressed in this dissertation both participates in and seeks to challenge the conditions and consequences of global capitalism by proposing modes of individual and collective resilience.</p