Article
Microbiology
Giancarlo Atassi, Rachel Medernach, Marc Scheetz, Sophia Nozick, Nathaniel J. Rhodes, Megan Murphy-Belcaster, Katherine R. Murphy, Arghavan Alisoltani, Egon A. Ozer, Alan R. Hauser
Summary: Resistance to aminoglycosides in Pseudomonas aeruginosa remained constant over 2 decades, indicating the effectiveness of antibiotic stewardship programs. Clinically relevant AME genes were found in 14% of isolates, and mutations in mexZ and armZ genes were common. These findings highlight the ongoing problem of aminoglycoside resistance and suggest potential targets for novel therapeutics.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Vicente Lopez-Chavarrias, Maria Ugarte-Ruiz, Carmen Barcena, Adolfo Olarra, Maria Garcia, Jose Luis Saez, Cristina de Frutos, Tania Serrano, Iratxe Perez, Miguel Angel Moreno, Lucas Dominguez, Julio Alvarez
Summary: The study found significant variations in antimicrobial resistance proportions to aminoglycosides and macrolides in C. coli and C. jejuni isolated from livestock at slaughterhouses in Spain. Additionally, a strong association was observed between the simultaneous presentation of resistance to both antimicrobial classes across different hosts. Further whole genome sequencing studies are needed to explore the epidemiological links between hosts and bacterial strains.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Immunology
Matas Griskaitis, Luis Furuya-Kanamori, Kasim Allel, Richard Stabler, Patrick Harris, David L. Paterson, Laith Yakob
Summary: This study aimed to determine whether the temporal dynamics of resistance emergence at the individual-patient level were predictable for specific pathogen-drug classes. It was found that beta-lactam-resistant Streptococcus pneumoniae peaked 4 days after treatment completion. The decline of resistance was slower compared to its emergence, returning to preexposure levels 1 month after treatment. Based on this finding, resistance surveillance should target this temporal peak.
CLINICAL INFECTIOUS DISEASES
(2022)
Article
Microbiology
Juliana Carolina Amorim, Juan Marcelo Carpio
Summary: The study identified alpha-naphthoflavone derivatives as potential inhibitors of EfAPH(3')-IIIa, suggesting that this core structure could be a promising scaffold for developing adjuvants that restore the sensitivity of aminoglycosides.
Article
Microbiology
Isabella Santi, Pablo Manfredi, Enea Maffei, Adrian Egli, Urs Jenal
Summary: The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. In the case of the human pathogen Pseudomonas aeruginosa, it has been shown that tolerance precedes and promotes the acquisition of resistance in vitro. This suggests that a thorough understanding of tolerance and resistance development is crucial for successfully combating antibiotic resistance.
Article
Infectious Diseases
Stacey S. Cherny, Daniel Nevo, Avi Baraz, Shoham Baruch, Ohad Lewin-Epstein, Gideon Y. Stein, Uri Obolski
Summary: The study analyzed clinical data and found strong associations between resistance to different antibiotics, not only within the same class but also across different bacterial species. Additionally, resistance to antibiotics was directly linked with previous antibiotic usage.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2021)
Article
Chemistry, Multidisciplinary
Meghan Rothenbroker, Erin M. McConnell, Jimmy Gu, Malene L. Urbanus, Sahar Esmaeili Samani, Alex W. Ensminger, Carlos D. M. Filipe, Yingfu Li
Summary: LP1 is an RNA-cleaving fluorogenic DNAzyme that is reactive with multiple infectious isolates of L. pneumophila, capable of generating a detectable signal for bacterial detection. It holds potential for the development of biosensors to monitor the contamination of L. pneumophila in exposure sources such as cooling towers.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biology
Hirdesh Kumar, Emily E. Williford, Kevin S. Blake, Brett Virgin-Downey, Gautam Dantas, Timothy A. Wencewicz, Niraj H. Tolia
Summary: This study reveals that anhydrotetracycline binds and inhibits type 1 tetracycline destructases (TDases) in a distinct manner compared to type 2 TDases. Inactivation of tetracycline antibiotics by TDases is a significant threat in clinical and agricultural settings. Anhydrotetracycline serves as a pan-TDase inhibitor that targets both type 1 and type 2 TDases. The findings provide valuable insights into the development of future therapies against enzymatic tetracycline resistance.
COMMUNICATIONS BIOLOGY
(2023)
Article
Chemistry, Medicinal
Duo Yuan, Shangde Liu, Shanshan Li, Rongrong Liu, Xiong Zhu
Summary: The evolution of drug-resistant bacteria is a serious threat to public health. This study focuses on developing new and efficient antibiotics to combat this issue. A series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (DAPQ) derivatives based on the dual-target antibacterial candidate IRS-16 were designed and synthesized. The most promising compound, 7-(4-(4-methylpiperazin-1-yl) benzyl)-7H-pyrrol[3,2-f] quinazoline-1,3-diamine (18 e), exhibited excellent antibacterial activity against both gram-positive and gram-negative bacteria, as well as improved solubility, low hemolytic activity, and cytotoxicity. Moreover, compound 18 e showed rapid bactericidal properties and prevented bacterial resistance in laboratory simulations, providing a basis for the development of new DAPQ-based compounds to combat emerging bacterial resistance.
Review
Chemistry, Medicinal
Yujie Gao, Yuan Chen, Yubin Cao, Anchun Mo, Qiang Peng
Summary: The abuse of antibiotics has led to the emergence of drug-resistant pathogens, such as MRSA, which presents a significant challenge in treatment. Nanotechnology offers a promising solution, utilizing functional nanomaterials as drug carriers or antibacterial agents for therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Amala Maxwell, Vivek Ghate, Jesil Aranjani, Shaila Lewis
Summary: Hypodermic delivery of amikacin is commonly used for severe infections, but faces challenges such as frequent dosing, prolonged hospitalization, and severe adverse effects. Novel controlled and sustained release drug delivery platforms may address these issues, enhance antibacterial activity, overcome drug resistance, and pave the way for future therapeutic interventions.
Review
Medicine, Research & Experimental
Tyler A. Le, Tasneem Hiba, Disha Chaudhari, Arielle N. Preston, Zachary R. Palowsky, Shahab Ahmadzadeh, Sahar Shekoohi, Elyse M. Cornett, Alan D. Kaye
Summary: Aminoglycosides are a group of drugs used for treating specific bacterial infections, particularly gram-negative aerobes. They can be used alone or in combination with other drugs. Aminoglycosides can have various formulations, such as oral, inhalants, intravascular, intramuscular, or intraventricular. While these drugs provide excellent coverage, they can cause nephrotoxicity and ototoxicity as common side effects. Research on the prevention and treatment of these adverse effects is limited, but future studies could expand the usage of aminoglycosides in modern medicine.
ADVANCES IN THERAPY
(2023)
Article
Chemistry, Medicinal
Bernd Kuhn, Wolfgang Haap, Ulrike Obst-Sander, Christian Kramer, Martin Stahl
Summary: Prof. Francois Diederich's consultancy work for Roche and collaboration with his research group at ETH Zurich have had a profound impact on shaping our approach to molecular design and enhancing our understanding of molecular recognition. His unique style and approach continue to inspire us in our work.
Article
Biochemistry & Molecular Biology
Adree Khondker, Renee-Claude Bider, Isabella Passos-Gastaldo, Gerard D. Wright, Maikel C. Rheinstadter
Summary: The study examined the interaction between different types of antibiotics and bacterial membranes, finding that the antibiotics increased membrane disorder without causing membrane damage. Antibiotics were observed to partition into lipid head groups, with some also partitioning into the bilayer core.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Chemistry, Medicinal
Emily E. Williford, Caitlin M. DeAngelo, Kevin S. Blake, Hirdesh Kumar, Kendrick K. Lam, Katherine V. Jones, Niraj H. Tolia, Gautam Dantas, Timothy A. Wencewicz
Summary: Tetracyclines (TCs) are a group of important antibiotics that are facing a new resistance mechanism called enzymatic inactivation. To overcome this resistance, combination therapies using TDase inhibitors and TC antibiotics are considered effective. In this study, we designed, synthesized, and evaluated bifunctional TDase inhibitors derived from anhydrotetracycline (aTC). The bisubstrate inhibitors showed enhanced interactions with TDases and blocked TC binding and the reduction of FAD by NADPH, thereby inhibiting the TDases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Alicia Asin, Fayna Garcia-Martin, Jesus Hector Busto, Alberto Avenoza, Jesus Manuel Peregrina, Francisco Corzana
Summary: Immunotherapy, especially using MUC1 glycopeptides as vaccine candidates, has shown promising results in cancer treatment. In this study, the researchers designed three vaccines based on MUC1 glycopeptides with unnatural elements in their structure. The vaccines were found to elicit strong immune responses in mice and produce antibodies that can recognize human cancer cells. The study suggests that effective MUC1-based vaccines should mimic the conformational space of aberrantly glycosylated MUC1 glycopeptides found in tumors.
CURRENT MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Paola Marzullo, Zlata Boiarska, Helena Perez-Pena, Anne-Catherine Abel, Beatriz Alvarez-Bernad, Daniel Lucena-Agell, Francesca Vasile, Maurizio Sironi, Karl-Heinz Altmann, Andrea E. Prota, J. Fernando Diaz, Stefano Pieraccini, Daniele Passarella
Summary: Maytansinol is a valuable precursor for the preparation of maytansine derivatives, and a series of novel derivatives with modifications of the maytansine scaffold were successfully obtained through acylation reaction. Characterization of these molecules by docking studies, biochemical evaluation, and determination of crystal structures in complex with tubulin shed further light on the chemical behavior of maytansinoids and confirm their relevance in the scenario of tubulin binders.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Medicinal
Giuseppe Campiani, Tuhina Khan, Cristina Ulivieri, Leopoldo Staiano, Chiara Papulino, Stefania Magnano, Seema Nathwani, Anna Ramunno, Daniel Lucena-Agell, Nicola Relitti, Stefano Federico, Luca Pozzetti, Gabriele Carullo, Alice Casagni, Simone Brogi, Francesca Vanni, Paola Galatello, Magda Ghanim, Niamh McCabe, Stefania Lamponi, Massimo Valoti, Ola Ibrahim, Jeffrey O'Sullivan, Richard Turkington, Vincent P. Kelly, Ruben VanWemmel, J. Fernando Diaz, Sandra Gemma, Daniela Zisterer, Lucia Altucci, Antonella De Matteis, Stefania Butini, Rosaria Benedetti
Summary: Autophagy, a crucial mechanism for maintaining organismal homeostasis, has become a focus in cancer therapy. In this study, new multifunctional agents with both pro-apoptotic and autophagy-inhibiting effects were designed and their therapeutic potential was demonstrated through experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Maria Angela Oliva, Carlota Tosat-Bitrian, Lucia Barrado-Gil, Francesca Bonato, Inmaculada Galindo, Urtzi Garaigorta, Beatriz Alvarez-Bernad, Rebeca Paris-Ogayar, Daniel Lucena-Agell, Juan Francisco Gimenez-Abian, Isabel Garcia-Dorival, Jesus Urquiza, Pablo Gastaminza, Jose Fernando Diaz, Valle Palomo, Covadonga Alonso
Summary: Microtubule targeting agents have potential in antiviral drug research, and some clinically used drugs have shown significant inhibitory effects on viral infections. However, their mechanism of action is complex and the relationship with intracellular transport is unclear.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Andres Manuel Gonzalez-Ramirez, Ana Sofia Grosso, Zhang Yang, Ismael Companon, Helena Coelho, Yoshiki Narimatsu, Henrik Clausen, Filipa Marcelo, Francisco Corzana, Ramon Hurtado-Guerrero
Summary: This study provides molecular insights into the function of C1GalT1, a glycosyltransferase that plays a key role in protein O-glycosylation. The crystal structure of the Drosophila enzyme-substrate complex reveals that C1GalT1 is an obligate GT-A fold dimer that follows a S(N)2 mechanism. The binding of glycopeptides to C1GalT1 is mainly driven by the GalNAc moiety, and the peptide sequence provides optimal kinetic and binding parameters. C1GalT1 recognizes a high-energy conformation of the alpha-GalNAc-Thr linkage to achieve glycosylation. These findings contribute to our understanding of glycosylation mechanisms adopted by glycosyltransferases.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Christian Paul Bold, Daniel Lucena-Agell, Maria Angela Oliva, Jose Fernando Diaz, Karl-Heinz Altmann
Summary: This study describes a new method for the total synthesis of the macrodiolide C(13)/C(13 ')-bis(desmethyl)disorazole Z, and demonstrates its binding to tubulin and inhibition of tubulin assembly, indicating a stronger cell growth inhibitory effect.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biochemistry & Molecular Biology
Ana Pozo-Rodriguez, Juan A. A. Mendez-Liter, Rocio Garcia-Villalba, David Beltran, Eva Calvino, Andres G. Santana, Laura I. I. De Eugenio, Francisco Javier Canada, Alicia Prieto, Jorge Barriuso, Francisco A. A. Tomas-Barberan, Maria Jesus Martinez
Summary: Resveratrol was glycosylated by using rXynSOS-E236G glycosynthase, resulting in the production of 3-O-beta-D-xylobiosyl resveratrol as the major product. Response surface methodology was used to optimize the reaction, yielding 35% of 3-O-beta-D-xylobiosyl resveratrol. Xylobiosylation decreased the antioxidant capacity of resveratrol, but significantly improved its solubility for improved delivery and transit to the colon.
Article
Chemistry, Multidisciplinary
Maria Angela Oliva, Federico Gago, Shinji Kamimura, J. Fernando Diaz
Summary: Microtubules are cellular machines with essential functions in cell shape, division, and intracellular transport. They are regulated chemically through GTP binding and hydrolysis, resulting in a cascade of structural changes known as MT maturation. Traditional structural biology methods, such as crystallography and cryo-electron microscopy, can be complemented by time-resolved fiber diffraction and computational modeling to gain a better understanding of MT assembly and dynamics. Studies on structurally similar tubulins from prokaryotes can also contribute novel insights.
Review
Chemistry, Multidisciplinary
Ignacio Sanz-Martinez, Sandra Pereira, Pedro Merino, Francisco Corzana, Ramon Hurtado-Guerrero
Summary: N-acetylgalactosamine (GalNAc) type O-glycosylation is a crucial posttranslational modification in biology. Malfunction of this modification is associated with truncated O-glycans in cancer. Understanding the structure and recognition of GalNAc-containing glycopeptides can contribute to the development of therapeutic vaccines and new diagnostic tools for cancer detection.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Tobias M. Bruetsch, Etienne Cotter, Daniel Lucena-Agell, Mariano Redondo-Horcajo, Carolina Davies, Bernhard Pfeiffer, Sandro Pagani, Simone Berardozzi, J. Fernando Diaz, John H. Miller, Karl-Heinz Altmann
Summary: In this study, five analogs of (-)-zampanolide (ZMP) were synthesized and their biochemical and cellular properties were evaluated. These analogs were derived from 13-desmethylene-(-)-zampanolide (DM-ZMP), which is as potent as ZMP in inhibiting cancer cell growth. Key steps in the synthesis of all compounds included the formation of a dioxabicyclo[15.3.1]heneicosane core and the establishment of the C(20) stereocenter. All modifications resulted in reduced cellular activity and microtubule-binding affinity compared to DM-ZMP, with varying degrees. The most potent analog, 2,3-dihydro-13-desmethylene zampanolide, showed cellular potency within a ninefold range of DM-ZMP.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Multidisciplinary Sciences
Itxaso Anso, Andreas Naegeli, Javier O. Cifuente, Ane Orrantia, Erica Andersson, Olatz Zenarruzabeitia, Alicia Moraleda-Montoya, Mikel Garcia-Alija, Francisco Corzana, Rafael A. Del Orbe, Francisco Borrego, Beatriz Trastoy, Jonathan Sjogren, Marcelo E. Guerin
Summary: Red blood cell antigens are critical in blood transfusion. Researchers have discovered a bacterial enzyme called FucOB that can convert universal O type blood into the rare Bombay type blood. This finding has the potential to facilitate transfusion in recipients with the Bombay phenotype.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Maria Pia Lenza, Leire Egia-Mendikute, Asier Antonana-Vildosola, Catia O. Soares, Helena Coelho, Francisco Corzana, Alexandre Bosch, Prodhi Manisha, Jon Imanol Quintana, Iker Oyenarte, Luca Unione, Maria Jesus Moure, Mikel Azkargorta, Unai Atxabal, Klaudia Sobczak, Felix Elortza, James D. Sutherland, Rosa Barrio, Filipa Marcelo, Jesus Jimenez-Barbero, Asis Palazon, June Ereno-Orbea
Summary: This study elucidates the structure and binding epitope of Siglec-15, providing insights into its mechanism of action and potential for cancer immunotherapy. The findings highlight the importance of glycosylation in controlling T cell responses and identify CD11b as a binding partner for Siglec-15 on human T cells.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Herwig Prasch, Andreas Wolfsgruber, Martin Thonhofer, Andre Culum, Christoph Mandl, Patrick Weber, Melanie Zuendel, Seyed A. Nasseri, Andres Gonzalez Santana, Gregor Tegl, Bernd Nidetzky, Karl Gruber, Arnold E. Stuetz, Stephen G. Withers, Tanja M. Wrodnigg
Summary: Selective covalent labelling of enzymes using small molecule probes has emerged as a powerful technique for protein profiling. This study demonstrates the use of ligand-directed chemistry (LDC) to label glycoside hydrolases near the active site without inhibiting their catalytic activity. The results suggest that LDC can be an adaptable approach for covalent proximity labelling of these enzymes.
Article
Multidisciplinary Sciences
Beatriz Piniello, Javier Macias-Leon, Shun Miyazaki, Ana Garcia-Garcia, Ismael Companon, Mattia Ghirardello, Victor Taleb, Billy Veloz, Francisco Corzana, Atsushi Miyagawa, Carme Rovira, Ramon Hurtado-Guerrero
Summary: In this study, the structures of soluble HMW1C-like N-glycosyltransferases (NGTs) were reported, revealing a key dyad of basic/acidic residues that plays a crucial role in Asn catalysis. The study also found that UDP-galactose and UDP-glucose mimetics act as poor substrates and inhibitors, impeding catalysis. QM/MM simulations provide insight into the reaction mechanism of AaNGT. These findings are important for understanding the mechanism of NGTs and designing drugs.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Maria Chatzinikolaidou, Cristina Nativi, Oscar Francesconi, Francisco Corzana, Georgia-Ioanna Kontogianni, Giorgio Pesciullesi, Roberta Gualdani, Claudiu T. Supuran, Andrea Angeli, Rafaela Maria Kavasi
Summary: This study describes the impact of a novel TRPA1 inhibitor on human osteosarcoma cells and demonstrates a potential new strategy for treating osteosarcomas.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)