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      New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action

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          Abstract

          This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin, very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl β-naphthylamide (PAβN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported.

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          Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

          Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. © 2011 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.
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            Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.

            Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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              Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.

              A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Antibiotics (Basel)
                Antibiotics (Basel)
                antibiotics
                Antibiotics
                MDPI
                2079-6382
                12 June 2021
                June 2021
                : 10
                : 6
                : 709
                Affiliations
                [1 ]Laboratory of Molecular Microbiology & Antimicrobials, Department of Pathology & Experimental Therapeutics, Medical School, University of Barcelona, Bellvitge Institute for Biomedical Research (IDIBELL), Hospitalet de Llobregat, 08907 Barcelona, Spain; mjorba@ 123456ub.edu (M.J.); rherraez@ 123456ub.edu (R.H.)
                [2 ]Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, Spain; mpedrola@ 123456ub.edu (M.P.); ghashghaei@ 123456ub.edu (O.G.); rlavilla@ 123456ub.edu (R.L.)
                [3 ]Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), Institute of Theoretical and Computational Chemistry (IQTC-UB), University of Barcelona, Av. Prat de la Riba 171, 08921 Santa Coloma de Gramenet, Spain; lluis.campos@ 123456pharmacelera.com (L.C.-V.); fjluque@ 123456ub.edu (F.J.L.)
                [4 ]Pharmacelera, Torre R, 4a planta, Despatx A05, Parc Científic de Barcelona, Baldiri Reixac 8, 08028 Barcelona, Spain
                Author notes
                [* ]Correspondence: mvinyas@ 123456ub.edu
                Author information
                https://orcid.org/0000-0002-8492-6331
                https://orcid.org/0000-0002-5524-3697
                https://orcid.org/0000-0002-8049-3567
                https://orcid.org/0000-0002-5006-9917
                https://orcid.org/0000-0003-2073-3386
                Article
                antibiotics-10-00709
                10.3390/antibiotics10060709
                8231229
                34204647
                f5870aff-610a-443b-86eb-69f727274e62
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 18 May 2021
                : 10 June 2021
                Categories
                Article

                trimethoprim,multidrug-resistant (mdr) bacteria,mechanisms of action,dihydrofolate reductase

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