The Development of the Bengamides as New Antibiotics against Drug-Resistant Bacteria

The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.Supported by grants RTI2018-098296-BI00 (Ministerio de Ciencia e Innovación), PI19/01478 from Instituto de Salud Carlos III (ISCIII) (FEDER), P20_00540 (Andalusian Government and FEDER), K99GM138758 and R35GM136286 (National Institute of General Medical Sciences of the National Institutes of Health), A-CTS-666-UGR20 (University of Granada) (FEDER), CTS-107 (Andalusian Government) and 2021-GRIN-30998 (University of Castilla-La Mancha). Partial funding for open access charge: Universidad de Málag

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase

Announcement of 2019 Keystone Symposia Conference: "Microbiome: Chemical Mechanisms and Biological Consequences".

The Keystone Symposia will be hosting a conference organized by Emily Balskus, Peter Turnbaugh, and Dennis Wolan entitled "Microbiome: Chemical Mechanisms and Biological Consequences" 10 to 14 March 2019 in Montreal, Québec, Canada. Our goal for this meeting is to focus attention on the intersection of chemistry and biology by bringing together scientists in these two disciplines, while also including talks about other hosts, environmental microbiomes, and multidisciplinary research platforms. The focus of this conference is to emphasize our community's need to continue adopting other scientific disciplines to ultimately generate a broad understanding of microbiomes and the cross talk microbes have with their environment. We are inviting speakers from across the globe that interrogate fundamental chemical processes of microbiomes, including small-molecule and xenobiotic metabolism, natural product synthesis, and the many microbial enzymes responsible for the production of these biologically relevant metabolites. The ability to link the chemical foundations of microbes with biological outcomes would provide tremendous contributions to this emerging field of study

Announcement of 2019 Keystone Symposia Conference: “Microbiome: Chemical Mechanisms and Biological Consequences”

The Keystone Symposia will be hosting a conference organized by Emily Balskus, Peter Turnbaugh, and Dennis Wolan entitled “Microbiome: Chemical Mechanisms and Biological Consequences” 10 to 14 March 2019 in Montreal, Québec, Canada. Our goal for this meeting is to focus attention on the intersection of chemistry and biology by bringing together scientists in these two disciplines, while also including talks about other hosts, environmental microbiomes, and multidisciplinary research platforms.The Keystone Symposia will be hosting a conference organized by Emily Balskus, Peter Turnbaugh, and Dennis Wolan entitled “Microbiome: Chemical Mechanisms and Biological Consequences” 10 to 14 March 2019 in Montreal, Québec, Canada. Our goal for this meeting is to focus attention on the intersection of chemistry and biology by bringing together scientists in these two disciplines, while also including talks about other hosts, environmental microbiomes, and multidisciplinary research platforms. The focus of this conference is to emphasize our community’s need to continue adopting other scientific disciplines to ultimately generate a broad understanding of microbiomes and the cross talk microbes have with their environment. We are inviting speakers from across the globe that interrogate fundamental chemical processes of microbiomes, including small-molecule and xenobiotic metabolism, natural product synthesis, and the many microbial enzymes responsible for the production of these biologically relevant metabolites. The ability to link the chemical foundations of microbes with biological outcomes would provide tremendous contributions to this emerging field of study

Fibrils Colocalize Caspase-3 with Procaspase-3 to Foster Maturation*

Most proteases are expressed as inactive precursors, or zymogens, that become activated by limited proteolysis. We previously identified a small molecule, termed 1541, that dramatically promotes the maturation of the zymogen, procaspase-3, to its mature form, caspase-3. Surprisingly, compound 1541 self-assembles into nanofibrils, and localization of procaspase-3 to the fibrils promotes activation. Here, we interrogate the biochemical mechanism of procaspase-3 activation on 1541 fibrils in addition to proteogenic amyloid-β(1-40) fibrils. In contrast to previous reports, we find no evidence that procaspase-3 alone is capable of self-activation, consistent with its fate-determining role in executing apoptosis. In fact, mature caspase-3 is >10(7)-fold more active than procaspase-3, making this proenzyme a remarkably inactive zymogen. However, we also show that fibril-induced colocalization of trace amounts of caspase-3 or other initiator proteases with procaspase-3 dramatically stimulates maturation of the proenzyme in vitro. Thus, similar to known cellular signaling complexes, these synthetic or natural fibrils can serve as platforms to concentrate procaspase-3 for trans-activation by upstream proteases

Proceedings du 23ème Conseil Solvay de Chimie "New Chemistry and New Opportunities from the Expanding Protein Universe": World Scientific Publishing

info:eu-repo/semantics/publishe

Discovery of a Highly Selective Caspase‑3 Substrate for Imaging Live Cells

Caspases are a family of cysteine proteases that are well-known for their roles in apoptosis and inflammation. Recent studies provide evidence that caspases are also integral to many additional cellular processes, such as differentiation and proliferation. Likewise, aberrant caspase activity has been implicated in the progression of several diseases, including neurodegenerative disorders, cancer, cardiovascular disease, and sepsis. These observations establish the importance of caspases to a diverse array of physiological functions and future endeavors will undoubtedly continue to elucidate additional processes that require caspase activity. Unfortunately, the existence of 11 functional human caspases, with overlapping substrate specificities, confounds the ability to confidently assign one or more isoforms to biological phenomena. Herein, we characterize a first-in-class FRET substrate that is selectively recognized by active caspase-3 over other initiator and executioner caspases. We further apply this substrate to specifically image caspase-3 activity in live cells undergoing apoptosis