Is the Bombali virus pathogenic in humans?

Motivation: The potential of the Bombali virus, a novel Ebolavirus, to cause disease in humans remains unknown. We have previously identified potential determinants of Ebolavirus pathogenicity in humans by analysing the amino acid positions that are differentially conserved (specificity 15 determining positions; SDPs) between human pathogenic Ebolaviruses and the non-pathogenic Reston virus. Here, we include the many Ebolavirus genome sequences that have since become available into our analysis and investigate the amino acid sequence of the Bombali virus proteins at the SDPs that discriminate between human pathogenic and non-human pathogenic Ebolaviruses. 20 Results: The use of 1408 Ebolavirus genomes (196 in the original analysis) resulted in a set of 166 SDPs (reduced from 180), 146 (88%) of which were retained from the original analysis. This indicates the robustness of our approach and refines the set of SDPs that distinguish human pathogenic Ebolaviruses from Reston virus. At SDPs, Bombali virus shared the majority of amino acids with the human pathogenic Ebolaviruses (63.25%). However, for two SDPs in VP24 (M136L, R139S) 25 that have been proposed to be critical for the lack of Reston virus human pathogenicity because they alter the VP24-karyopherin interaction, the Bombali virus amino acids match those of Reston virus. Thus, Bombali virus may not be pathogenic in humans. Supporting this, no Bombali virusassociated disease outbreaks have been reported, although Bombali virus was isolated from fruit bats cohabitating in close contact with humans, and anti-Ebolavirus antibodies that may indicate 30 contact with Bombali virus have been detected in humans

Identification of a novel DNA repair inhibitor using an in silico driven approach shows effective combinatorial activity with genotoxic agents against multidrug-resistant Escherichia coli

Increasing antimicrobial drug resistance represents a global existential threat. Infection is a particular problem in immunocompromised individuals, such as patients undergoing cancer chemotherapy, due to the targeting of rapidly dividing cells by antineoplastic agents. We recently developed a strategy that targets bacterial nucleotide excision DNA repair (NER) to identify compounds that act as antimicrobial sensitizers specific for patients undergoing cancer chemotherapy. Building on this, we performed a virtual drug screening of a ~120,000 compound library against the key NER protein UvrA. From this, numerous target compounds were identified and of those a candidate compound, Bemcentinib (R428), showed a strong affinity toward UvrA. This NER protein possesses four ATPase sites in its dimeric state, and we found that Bemcentinib could inhibit UvrA's ATPase activity by ~90% and also impair its ability to bind DNA. As a result, Bemcentinib strongly diminishes NER's ability to repair DNA in vitro. To provide a measure of in vivo activity we discovered that the growth of Escherichia coli MG1655 was significantly inhibited when Bemcentinib was combined with the DNA damaging agent 4-NQO, which is analogous to UV. Using the clinically relevant DNA-damaging antineoplastic cisplatin in combination with Bemcentinib against the urological sepsis-causing E. coli strain EC958 caused complete growth inhibition. This study offers a novel approach for the potential development of new compounds for use as adjuvants in antineoplastic therapy

PDBe-KB: a community-driven resource for structural and functional annotations.

The Protein Data Bank in Europe-Knowledge Base (PDBe-KB, https://pdbe-kb.org) is a community-driven, collaborative resource for literature-derived, manually curated and computationally predicted structural and functional annotations of macromolecular structure data, contained in the Protein Data Bank (PDB). The goal of PDBe-KB is two-fold: (i) to increase the visibility and reduce the fragmentation of annotations contributed by specialist data resources, and to make these data more findable, accessible, interoperable and reusable (FAIR) and (ii) to place macromolecular structure data in their biological context, thus facilitating their use by the broader scientific community in fundamental and applied research. Here, we describe the guidelines of this collaborative effort, the current status of contributed data, and the PDBe-KB infrastructure, which includes the data exchange format, the deposition system for added value annotations, the distributable database containing the assembled data, and programmatic access endpoints. We also describe a series of novel web-pages-the PDBe-KB aggregated views of structure data-which combine information on macromolecular structures from many PDB entries. We have recently released the first set of pages in this series, which provide an overview of available structural and functional information for a protein of interest, referenced by a UniProtKB accession

Steroid drugs inhibit bacterial respiratory oxidases and are lethal towards methicillin-resistant Staphylococcus aureus

Background: Cytochrome bd complexes are respiratory oxidases found exclusively in prokaryotes that are important during infection for numerous bacterial pathogens. Methods: In silico docking was employed to screen approved drugs for their ability to bind to the quinol site of Escherichia coli cytochrome bd-I. Respiratory inhibition was assessed with oxygen electrodes using membranes isolated from E. coli and Methicillin-resistant Staphylococcus aureus strains expressing single respiratory oxidases (i.e., cytochromes bd, bo or aa3). Growth/viability assays were used to measure bacteriostatic and bactericidal effects. Results: The steroid drugs ethinylestradiol and quinestrol inhibited E. coli bd-I activity with IC50 values of 47 ± 28.9 µg/mL (158 ± 97.2 µM) and 0.2 ± 0.04 µg/mL (0.5 ± 0.1 µM), respectively. Quinestrol inhibited growth of an E. coli ‘bd-I only’ strain with an IC50 of 0.06 ± 0.02 µg/mL (0.2 ± 0.07 µM). Growth of a S. aureus ‘bd only’ strain was inhibited by quinestrol with an IC50 of 2.2 ± 0.43 µg/mL (6.0 ± 1.2 µM). Quinestrol exhibited potent bactericidal effects against S. aureus but not E. coli. Conclusions: Quinestrol inhibits cytochrome bd in E. coli and S. aureus membranes and inhibits the growth of both species yet is only bactericidal towards S. aureus

PDBe-KB: collaboratively defining the biological context of structural data

none71: The Protein Data Bank in Europe - Knowledge Base (PDBe-KB, https://pdbe-kb.org) is an open collaboration between world-leading specialist data resources contributing functional and biophysical annotations derived from or relevant to the Protein Data Bank (PDB). The goal of PDBe-KB is to place macromolecular structure data in their biological context by developing standardised data exchange formats and integrating functional annotations from the contributing partner resources into a knowledge graph that can provide valuable biological insights. Since we described PDBe-KB in 2019, there have been significant improvements in the variety of available annotation data sets and user functionality. Here, we provide an overview of the consortium, highlighting the addition of annotations such as predicted covalent binders, phosphorylation sites, effects of mutations on the protein structure and energetic local frustration. In addition, we describe a library of reusable web-based visualisation components and introduce new features such as a bulk download data service and a novel superposition service that generates clusters of superposed protein chains weekly for the whole PDB archive.noneVaradi, Mihaly; Anyango, Stephen; Armstrong, David; Berrisford, John; Choudhary, Preeti; Deshpande, Mandar; Nadzirin, Nurul; Nair, Sreenath S; Pravda, Lukas; Tanweer, Ahsan; Al-Lazikani, Bissan; Andreini, Claudia; Barton, Geoffrey J; Bednar, David; Berka, Karel; Blundell, Tom; Brock, Kelly P; Carazo, Jose Maria; Damborsky, Jiri; David, Alessia; Dey, Sucharita; Dunbrack, Roland; Recio, Juan Fernandez; Fraternali, Franca; Gibson, Toby; Helmer-Citterich, Manuela; Hoksza, David; Hopf, Thomas; Jakubec, David; Kannan, Natarajan; Krivak, Radoslav; Kumar, Manjeet; Levy, Emmanuel D; London, Nir; Macias, Jose Ramon; Srivatsan, Madhusudhan M; Marks, Debora S; Martens, Lennart; McGowan, Stuart A; McGreig, Jake E; Modi, Vivek; Parra, R Gonzalo; Pepe, Gerardo; Piovesan, Damiano; Prilusky, Jaime; Putignano, Valeria; Radusky, Leandro G; Ramasamy, Pathmanaban; Rausch, Atilio O; Reuter, Nathalie; Rodriguez, Luis A; Rollins, Nathan J; Rosato, Antonio; Rubach, Paweł; Serrano, Luis; Singh, Gulzar; Skoda, Petr; Sorzano, Carlos Oscar S; Stourac, Jan; Sulkowska, Joanna I; Svobodova, Radka; Tichshenko, Natalia; Tosatto, Silvio C E; Vranken, Wim; Wass, Mark N; Xue, Dandan; Zaidman, Daniel; Thornton, Janet; Sternberg, Michael; Orengo, Christine; Velankar, SameerVaradi, Mihaly; Anyango, Stephen; Armstrong, David; Berrisford, John; Choudhary, Preeti; Deshpande, Mandar; Nadzirin, Nurul; Nair, Sreenath S; Pravda, Lukas; Tanweer, Ahsan; Al-Lazikani, Bissan; Andreini, Claudia; Barton, Geoffrey J; Bednar, David; Berka, Karel; Blundell, Tom; Brock, Kelly P; Carazo, Jose Maria; Damborsky, Jiri; David, Alessia; Dey, Sucharita; Dunbrack, Roland; Recio, Juan Fernandez; Fraternali, Franca; Gibson, Toby; Helmer-Citterich, Manuela; Hoksza, David; Hopf, Thomas; Jakubec, David; Kannan, Natarajan; Krivak, Radoslav; Kumar, Manjeet; Levy, Emmanuel D; London, Nir; Macias, Jose Ramon; Srivatsan, Madhusudhan M; Marks, Debora S; Martens, Lennart; Mcgowan, Stuart A; Mcgreig, Jake E; Modi, Vivek; Parra, R Gonzalo; Pepe, Gerardo; Piovesan, Damiano; Prilusky, Jaime; Putignano, Valeria; Radusky, Leandro G; Ramasamy, Pathmanaban; Rausch, Atilio O; Reuter, Nathalie; Rodriguez, Luis A; Rollins, Nathan J; Rosato, Antonio; Rubach, Paweł; Serrano, Luis; Singh, Gulzar; Skoda, Petr; Sorzano, Carlos Oscar S; Stourac, Jan; Sulkowska, Joanna I; Svobodova, Radka; Tichshenko, Natalia; Tosatto, Silvio C E; Vranken, Wim; Wass, Mark N; Xue, Dandan; Zaidman, Daniel; Thornton, Janet; Sternberg, Michael; Orengo, Christine; Velankar, Samee