Recently developed synthetic compounds with anti-infective activity

The ability of antibiotics to cure bacterial infections is at a serious risk due to the emergence and worldwide spread of superbugs. A lack of innovation and investment for almost 50 years has led to significant efforts currently being devoted to find alternative and innovative therapies to face this challenge. This short review highlights some of the recent efforts to develop synthetic small molecules with anti-infective activity. This article is focused on those compounds that, when co-administered with an antibiotic, enhance the antimicrobial action of the drug, as well as compounds that target unexplored objectives for bacterial survival. Selected examples are provided.Financial support from the Spanish Ministry of Economy andCompetiveness (SAF2016-75638-R), the Xunta de Galicia [Centro Singularde Investigación de Galicia accreditation 2016–2019 (ED431G/09) andED431B 2018/04] and the European Union (European RegionalDevelopment Fund – ERDF is gratefully acknowledgedS

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions - cell wall, DNA, RNA, and protein biosynthesis - and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is describedFinancial support from the Spanish Ministry of Science and Innovation (SAF2013-42899-R), Xunta de Galicia (GRC2013-041) and the European Regional Development Fund (ERDF) is gratefully acknowledgedS

Antibiotic adjuvants – A strategy to unlock bacterial resistance to antibiotics

Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the number of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has spread worldwide. To unlock this problem, the use of an ‘antibiotic adjuvant’ in combination with an antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those compounds that are already in clinical development, namely b-lactamase inhibitorsFinancial support from the Spanish Ministry of Economy and Competiveness (SAF2016-75638-R), the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09) and the European Union (European Regional Development Fund – ERDF) is gratefully acknowledgedS

Specific chemical modification of bacterial type I dehydroquinase – opportunities for drug discovery

Type I dehydroquinase (DHQ1) is a class I aldolase enzyme that catalyzes the reversible dehydration of 3-dehydroquinic acid to form 3-dehydroshikimic acid by multistep mechanism that involves the formation of Schiff-base species. DHQ1 is present in plants and several bacterial sources but it does not have any counterpart in human cells. It has been suggested that DHQ1 may act as a virulence factor in vivo and therefore a promising target in the search for new antivirulence agents to combat widespread antibiotic resistance. This review covers recent progress in the structure-based design and chemical modifications caused by selective irreversible inhibitors. Computational studies aimed at understanding the experimentally obtained covalent modifications and inhibitory potencies of these inhibitors are also describedFinancial support from the Spanish Ministry of Science and Innovation (SAF2013-42899-R), Xunta de Galicia (GRC2013-041) and the European Regional Development Fund (ERDF) is gratefully acknowledgedS

Freezing the Dynamic Gap for Selectivity: Motion‐Based Design of Inhibitors of the Shikimate Kinase Enzyme

This is the peer-reviewed version of the following article: Prado, V., Lence, E., Thompson, P., Hawkins, A., & González-Bello, C. (2016). Freezing the Dynamic Gap for Selectivity: Motion-Based Design of Inhibitors of the Shikimate Kinase Enzyme. Chemistry - A European Journal, 22(50), 17988-18000, which has been published in final form at https://doi.org/10.1002/chem.201602923. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingShikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5‐aminoshikimic acid and the natural substrate enhances the selectivity for the H. pylori enzyme due to key motion differences in the shikimic acid binding domain (mainly helix α5). These studies show that the less‐exploited motion‐based design approach not only is an alternative strategy for the development of competitive inhibitors, but could also be a way to achieve selectivity against a particular enzyme among its homologuesSpanish Ministry of Economy and Competiveness. Grant Number: SAF2013-42899-R Xunta de Galicia. Grant Number: GRC2013-041 European Regional Development Fund (ERDF) Spanish Ministry of Economy and Competiveness Xunta de GaliciaS

A combined photophysical and computational study on the binding of mycophenolate mofetil and its major metabolite to transport proteins

[EN] Binding of the inmunodrepresive agent mycophenolate mofetil (MMP) and its pharmacologically active metabolite mycophenolic acid (MPA) to human serum albumin (HSA) and ¿1-acid glycoprotein (HAAG) has been investigated by an integrated approach involving selective excitation of the drug fluorophore, following their UV-A triggered fluorescence and docking studies. The formation of the protein/ligand complexes was evidenced by a dramatic enhancement of the fluorescence intensity and a hypsochromic shift of the emission band. In HSA, competitive studies using oleic acid as site I probe revealed site I as the main binding site of the ligands. Binding constants revealed that the affinity of the active metabolite by HSA is four-fold higher than its proactive form. Moreover, the affinity of MMP by HSA is three-fold higher than by HAAG. Docking studies revealed significant molecular binding differences in the binding of MMP and MPA to sub-domain IIA of HSA (site 1). For MPA, the aromatic moiety would be in close contact to Trp214 with the flexible chain pointing to the other end of the sub-domain; on the contrary, for MMP, the carboxylate group of the chain would be fixed nearby Trp214 through electrostatic interactions with residues Arg218 and Arg222.Financial support from the Spanish Ministry of Economy and Competiveness (CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2016-75638-R), the Xunta de Galicia (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09), the European Union (European Regional Development Fund-ERDF) and the Generalitat Valenciana (PROMETEO/2017/075) is gratefully acknowledgedVendrell-Criado, V.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2018). A combined photophysical and computational study on the binding of mycophenolate mofetil and its major metabolite to transport proteins. Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy. 199:308-314. https://doi.org/10.1016/j.saa.2018.03.064S30831419

Eficiencia, interdisciplina y responsabilidad social en el diseño editorial: aproximaciones teóricas

From graphic design, various contributions and theoretical notions of the disciplinary field are addressed, and corresponding to professional practice. Desde el diseño gráfico, se aborda diversas aportaciones y nociones teóricas del campo disciplinar, y correspondientes al ejercicio profesional. A partir do design gráfico são abordadas várias contribuições e noções teóricas do campo disciplinar, correspondentes à prática profissional

Total Hydrolysis of a New Imidazolidine Induced by ZnII

The 18th International Electronic Conference on Synthetic Organic Chemistry session General Organic Synthesis2,2´-(2-(2-hydroxyphenyl)imidazolidin-1,3-diyl)diethanol(H3L) was obtained by condensation between 2-hydroxybenzaldehyde and N,N'-bis(2-hydroxyethyl)ethylenediamine. Its potential ability as NNOOO donor towards ZnII was tested. This study shows that zinc(II) mediates the fast hydrolysis of H3L, yielding the free aldehyde and amine. This latter was crystallographically characterised, showing a supramolecular 1D architecture based on hydrogen bond interaction

Synthesis of rigidified shikimic acid derivatives by ring-closing metathesis to imprint inhibitor efficacy against shikimate kinase enzyme

Diverse rigidified shikimic acids derivatives, which are stable mimetics of the high-energy conformation of shikimic acid, have been synthesized to enhance inhibitor efficacy against shikimate kinase enzyme (SK), an attractive target for antibiotic drug discovery. The synthesis of the reported conformationally restricted shikimic acid derivatives was carried out by ring-closing metathesis of allyloxy vinyl derivatives as the key step. The rigidification of the ligand conformation was used to maximize the effectiveness of the substituents introduced in the ether carbon bridge of the scaffold by pre-orienting their interaction with key residues and enzyme domains that are essential for catalysis and enzyme motion. Molecular Dynamics simulation studies on the enzyme/ligand complexes revealed marked differences in the positioning of the ligand substituent in the active site of the two enzymes studied (SK from Mycobacterium tuberculosis and Helicobacter pylori) and this explains their greater efficacy against one of the enzymes. This enhancement is due to the distinct induced-fit motion of the two homologous enzymes. A 20-fold improvement against the H. pylori enzyme was achieved by the introduction of a CH2OEt group in the rigid ether bridge of the reported shikimic acid analogsFinancial support from the Spanish Ministry of Economy and Competiveness (SAF2016-75638-R), the Xunta de Galicia [Centro singular de investigación de Galicia accreditation 2016–2019 (ED431G/09) and ED431B 2018/04], and the European Union (European Regional Development Fund –ERDF) is gratefully acknowledged. MP and EL thank the Xunta de Galicia for their respective predoctoral and postdoctoral fellowshipsS

Mechanistic insight into the reaction catalysed by bacterial type II dehydroquinases

DHQ2 (type II dehydroquinase), which is an essential enzyme in Helicobacter pylori and Mycobacterium tuberculosis and does not have any counterpart in humans, is recognized to be an attractive target for the development of new antibacterial agents. Computational and biochemical studies that help understand in atomic detail the catalytic mechanism of these bacterial enzymes are reported in the present paper. A previously unknown key role of certain conserved residues of these enzymes, as well as the structural changes responsible for triggering the release of the product from the active site, were identified. Asp89*/Asp88* from a neighbouring enzyme subunit proved to be the residue responsible for the deprotonation of the essential tyrosine to afford the catalytic tyrosinate, which triggers the enzymatic process. The essentiality of this residue is supported by results from site-directed mutagenesis. For H. pylori DHQ2, this reaction takes place through the assistance of a water molecule, whereas for M. tuberculosis DHQ2, the tyrosine is directly deprotonated by the aspartate residue. The participation of a water molecule in this deprotonation reaction is supported by solvent isotope effects and proton inventory studies. MD simulation studies provide details of the required motions for the catalytic turnover, which provides a complete overview of the catalytic cycle. The product is expelled from the active site by the essential arginine residue and after a large conformational change of a loop containing two conserved arginine residues (Arg109/Arg108 and Arg113/Arg112), which reveals a previously unknown key role for these residues. The present study highlights the key role of the aspartate residue whose blockage could be useful in the rational design of inhibitors and the mechanistic differences between both enzymesFinancial support from the Comunidad de Madrid (S2010-BMD-2457 to F.G.), Xunta de Galicia (10PXIB2200122PR and GRC2010/12 to C.G.-B.) and the Spanish Ministry of Science and Innovation (SAF2009-13914-C02-02 to F.G. and SAF2010-15076 to C.G.-B.) is 5076 to CGB and BFU2008-01588/BMC to MJvR) is gratefully acknowledged. C.C. and A.P. thank the Spanish Ministry of Science and Innovation for their respective FPU fellowshipsS