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Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

Natural products have a rich history of antimicrobial use. Chemodiversity and complexity of these structures often culminate in unique biological properties. Divergent and convergent synthetic approaches allow rapid diversification of natural product core scaffolds to evaluate the influence of structure on biological activity. The first chapter provides insight on antimicrobial development inspired by natural products, isolation of novel bioactive natural products, and synthetic approaches to generate compound libraries to evaluate key chemical moieties involved in microbial inhibition. The second chapter describes the synthesis of phenolic bisabolanes isolated from deep sea sediment that display potent activity towards microbial pathogens. Despite structural similarities, these natural products are reported to have narrow spectrum bioactivity suggesting minor changes in structure can result in unique mechanisms of action. Initially, the chapter focuses on the synthesis of peniciaculin A, a natural product with reported species specific activity against the plant fungal pathogen Alternaria brassicae. Investigations of the unique reported bioactivity leveraging synthetic derivatives of the natural product suggest peniciaculin A may be inhibiting fungal growth as a ubiquinone mimic. Identification of a key transformation in the synthesis of peniciaculin A allowed for rapid generation of 1-hydroxyboivinianin A, a lactone derivative with reported species specific activity against aquatic bacteria Vibrio harveyi. The third chapter explores the development of a common intermediate strategy for the synthesis of antifungal natural products, the purpurides. A key tricyclic intermediate was accessed through a tethered intramolecular Diels-Alder cycloaddition. The desired trans bicyclic system was synthesized via heterogeneous hydrogen atom transfer. Notably, heterogeneous catalysis provided solely cis isomer, invalidating previous reports of obtaining the trans isomer of analogous systems using this approach.The fourth chapter investigates natural product metabolites as narrow spectrum antimicrobial agents. Epoxy isonitrile containing natural products demonstrate specific and potent antibacterial activity against gram-positive pathogens, in particular Staphylococcus aureus. This scaffold, however, is extremely labile under acidic and basic conditions, undergoing a Payne rearrangement to produce a stable epoxy ketone metabolite and releasing hydrogen cyanide. Toxicity associated with the release of hydrogen cyanide renders these molecules unusable as antibiotics. When compared to the activity of sodium cyanide in vivo, epoxy isonitriles, including amycomicin, aerocyandin, and YM-47515, were shown to be more potent. Thus, the epoxy isonitriles were thought to act as prodrugs, undergoing the Payne rearrangement to produce active epoxy ketone metabolites. These metabolites would not only reduce the toxicity of the parent compounds by eliminating the release of hydrogen cyanide, but could be accessed via a more facile synthetic route. We synthesized and performed biological assays with epoxy ketone containing metabolites and identified that the epoxy isonitrile moiety is pertinent for biological activity. Serendipitously, we discovered an α,β-unsaturated epoxy ketone analogue that exhibited moderate activity against S. aureus.The fifth chapter includes discussion of a subpopulation of bacteria, persisters. Diminished response to antibacterials is often exacerbated by the presence of persister or metabolically dormant populations of bacteria. Membrane perturbing small molecules have the potential to eliminate persister populations, but use has been limited due to the low selectivity of these compounds for bacterial over mammalian membranes. Bithionol, a previously approved anthelmintic drug, is shown to inhibit methicillin-resistant Staphylococcus aureus (MRSA) persister cells via disruption of the membrane lipid bilayer at nontoxic levels to mammalian cells. Investigation of the structure activity relationship of bithionol and its tendency to interact with bacterial membranes suggests bioactivity correlates with the ability to increase membrane fluidity. This work demonstrates that membrane perturbing small molecules can be selective antibacterial agents and further investigations of this mechanism of action is warranted.

Myxofibrosarcoma (MFS) is a rare mesenchymal soft tissue sarcoma type, with a high local recurrence (LR) rate. Robust epidemiological data on MFS are lacking. We, therefore, aimed to identify prognostic factors and describe real-life outcomes of a large cohort of 908 MFS patients obtained from the nationwide database of the Netherlands Cancer Registry and diagnosed between 2002 and 2019. Median Overall survival (OS) was 155 (range 0.1–215) months, with a five-year OS of 67.7%. No improvement of OS was found over time. Multivariable Cox regression survival analysis demonstrated known prognostic factors for OS, such as older age, tumour size, and histological grade with the addition of sex. Surgery at sarcoma expertise centres, instead of general hospitals, was associated with better OS outcomes. In a subcohort of 177 patients, 39% developed LR with a median time to recurrence of 20 months. From LR on, the median OS was 64.0 months (CI 95% 38.5–89.5). In 28%, distant metastases were diagnosed with a median OS of 34.3 months (CI 95% 28.8–39.8) after diagnosis of the primary tumour. In this largest nationwide cohort so far, survival outcomes and recurrence rates for MFS patients did not improve over time, emphasizing the need to improve treatment strategies and suggesting a role for sarcoma expertise centres.