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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Exploring the SAR of the β-ketoacyl-ACP synthase inhibitor GSK3011724a and optimization around a genotoxic metabolite Fraser Cunningham , Jorge Esquivias , Raquel Fernández-menéndez , Arancha Pérez , Ana Guardia , Jaime Escribano , Cristina Rivero , Mythily Vimal , Mónica Cacho , Paco De Dios-antón , María Santos Martínez-martínez , Elena Jiménez , Leticia Huertas Valentín , María José Rebollo-lópez , Eva María López-román , Verónica Sousa-morcuende , Joaquín Rullas , Margaret Neu , Chun-wa Chung , Robert H. Bates Acs Infectious Diseases DOI: 10.1021/acsinfecdis.9b00493 Diamond Proposal Number(s): [5799] Show Abstract ▼ Abstract: In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.	Mar 2020
I04-Macromolecular Crystallography	Broad spectrum β-lactamase inhibition by a thioether substituted bicyclic boronate Anete Parkova , Anka Lucic , Alen Krajnc , Jurgen Brem , Karina Calvopina , Gareth Langley , Michael A. Mcdonough , Peteris Trapencieris , Christopher J. Schofield Acs Infectious Diseases DOI: 10.1021/acsinfecdis.9b00330 Show Abstract ▼ Abstract: β-Lactamases comprise the most important known mode of resistance to β-lactam antibiotics. Boronic acids/boronate esters show promise as a new class of β-lactamase inhibitors with the potential to inhibit both the metallo- and serine-β-lactamases. We report studies employing representative β-lactamases concerning a bicyclic boronate ester with a thioether rather than the more typical β-lactam antibiotic ‘C-6/C-7’ acylamino side chain as present in the penicillin/cephalosporin antibiotics. The results, including a crystal structure of the clinically relevant VIM-2 metallo β-lactamase in complex with the inhibitor, reveal the potential of boronate inhibitors without the canonical acylamino side chain for inhibition of a broader range of serine- and metallo- β-lactamases compared to previous bicyclic boronates, including the metallo-β-lactamase L1. They imply further SAR studies will expand the already broad scope of -lactamase inhibition by bicyclic boronates.	Dec 2019
I02-Macromolecular Crystallography	Structural insights into the development of cycloguanil derivatives as Trypanosoma brucei pteridine reductase 1 inhibitors Giacomo Landi , Pasquale Linciano , Chiara Borsari , Claudia P. Bertolacini , Carolina Borsoi Moraes , Anabela Cordeiro-da-silva , Sheraz Gul , Gesa Witt , Maria Kuzikov , Maria Paola Costi , Cecilia Pozzi , Stefano Mangani Acs Infectious Diseases DOI: 10.1021/acsinfecdis.8b00358 Diamond Proposal Number(s): [11690] Show Abstract ▼ Abstract: Cycloguanil is a known dihydrofolate reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was develop, resulting in 1 and 2a having IC50 of 692 and 186 nM, respectively, towards TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds and halogen bonds. Moreover, in vitro cell growth inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a new promising strategy for the treatment of human African Trypanosomiasis. On this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.	Apr 2019
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	SAR studies leading to the identification of a novel series of metallo-β-lactamase inhibitors for the treatment of carbapenem-resistant Enterobacteriaceae infections that display efficacy in an animal infection model Simon Leiris , Alicia Coelho , Jérôme Castandet , Maëlle Bayet , Clarisse Lozano , Juliette Bougnon , Justine Bousquet , Martin John Everett , Marc Lemonnier , Nicolas Sprynski , Magdalena Zalacain , Thomas David Pallin , Michael Cramp , Neil Jennings , Gilles Raphy , Mark William Jones , Ramesh Pattipati , Battu Shankar , Relangi Sivasubrahmanyam , Ashok Kumar Soodhagani , Ramakrishna Reddy Juventhala , Narender Pottabathini , Srinivasu Pothukanuri , Manuela Benvenuti , Cecilia Pozzi , Stefano Mangani , Filomena De Luca , Giulia Cerboni , Jean-denis Docquier , David Davies Acs Infectious Diseases DOI: 10.1021/acsinfecdis.8b00246 Diamond Proposal Number(s): [8574, 15832] Show Abstract ▼ Abstract: The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo β-lactamase (MBL) and serine β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein we describe our initial exploration of a novel chemical series of metallo β-lactamase inhibitors, from concept through to efficacy in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.	Nov 2018
	Getting drugs into Gram-negative bacteria: Rational rules for permeation through general porins Silvia Acosta-gutierrez , Luana Ferrara , Monisha Pathania , Muriel Masi , Jiajun Wang , Igor Bodrenko , Michael Zahn , Mathias Winterhalter , Robert A. Stavenger , Jean-marie Pages , James H. Naismith , Bert Van Den Berg , Malcolm G. P. Page , Matteo Ceccarelli Acs Infectious Diseases DOI: 10.1021/acsinfecdis.8b00108 Show Abstract ▼ Abstract: Small, hydrophilic molecules, including most important antibiotics in clinical use, cross the Gram-negative outer membrane through the water-filled channels provided by porins. We have determined the X-ray crystal structures of the principal general porins from three species of Enterobacteriaceae, namely Enterobacter aerogenes, Enterobacter cloacae and Klebsiella pneumoniae and determined their antibiotic permeabilities as well as those of the orthologues from Escherichia coli. Starting from the structure of the porins and molecules we propose a physical mechanism underlying transport and condense it in a computationally efficient scoring function. The scoring function shows good agreement with in-vitro penetration data and will enable the screening of virtual databases to identify molecules with optimal permeability through porins and help to guide the optimization of antibiotics with poor permeation.	Jul 2018
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani Leah S. Torrie , Stephen Brand , David A. Robinson , Eun Jung Ko , Laste Stojanovski , Frederick R. C. Simeons , Susan Wyllie , John Thomas , Lucy Ellis , Maria Osuna-cabello , Ola Epemolu , Andrea Nühs , Jennifer Riley , Lorna Maclean , Sujatha Manthri , Kevin D. Read , Ian H. Gilbert , Alan H. Fairlamb , Manu De Rycker Acs Infectious Diseases DOI: 10.1021/acsinfecdis.7b00047 Diamond Proposal Number(s): [8268] Show Abstract ▼ Abstract: Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study, we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust high-throughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki of 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately, this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable antileishmanial compound, MetRS remains an attractive antileishmanial drug target.	Oct 2017
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis Yumi Park , Angela Pacitto , Tracy Bayliss , Laura A. T. Cleghorn , Zhe Wang , Travis Hartman , Kriti Arora , Thomas R. Ioerger , Jim Sacchettini , Menico Rizzi , Stefano Donini , Tom L. Blundell , David B. Ascher , Kyu Rhee , Ardala Breda , Nian Zhou , Veronique Dartois , Surendranadha Reddy Jonnala , Laura E. Via , Valerie Mizrahi , Ola Epemolu , Laste Stojanovski , Fred Simeons , Maria Osuna-cabello , Lucy Ellis , Claire J. Mackenzie , Alasdair R. C. Smith , Susan H. Davis , Dinakaran Murugesan , Kirsteen I. Buchanan , Penelope A. Turner , Margaret Huggett , Fabio Zuccotto , Maria Jose Rebollo-lopez , Maria Jose Lafuente-monasterio , Olalla Sanz , Gracia Santos Diaz , Joël Lelièvre , Lluis Ballell , Carolyn Selenski , Matthew Axtman , Sonja Ghidelli-disse , Hannah Pflaumer , Markus Bösche , Gerard Drewes , Gail M. Freiberg , Matthew D. Kurnick , Myron Srikumaran , Dale J. Kempf , Simon R. Green , Peter C. Ray , Kevin Read , Paul Wyatt , Clifton E. Barry , Helena I. Boshoff Acs Infectious Diseases DOI: 10.1021/acsinfecdis.6b00103 Diamond Proposal Number(s): [9537] Show Abstract ▼ Abstract: A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH–IMP–inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi–pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time–kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5–2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.	Oct 2016
I24-Microfocus Macromolecular Crystallography	The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis Vinayak Singh , Stefano Donini , Angela Pacitto , Claudia Sala , Ruben C. Hartkoorn , Neeraj Dhar , Gyorgy Keri , David B. Ascher , Guillaume Mondésert , Anthony Vocat , Andréanne Lupien , Raphael Sommer , Hélène Vermet , Sophie Lagrange , Joe Buechler , Digby F. Warner , John D. Mckinney , Janos Pato , Stewart T. Cole , Tom L. Blundell , Menico Rizzi , Valerie Mizrahi Acs Infectious Diseases DOI: 10.1021/acsinfecdis.6b00102 Diamond Proposal Number(s): [9537] Show Abstract ▼ Abstract: VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library. Sequencing of a VCC234718-resistant mutant identified a Y487C substitution in the inosine monophosphate dehydrogenase, GuaB2, which was subsequently validated to be the primary molecular target of VCC234718 in Mtb. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD+. This compound binds at the NAD+ site, after IMP has bound, and makes direct interactions with IMP; therefore, the inhibitor is by definition uncompetitive. VCC234718 forms strong pi interactions with the Y487 residue side chain from the adjacent protomer in the tetramer, explaining the resistance-conferring mutation. In addition to sensitizing Mtb to VCC234718, depletion of GuaB2 was bactericidal in Mtb in vitro and in macrophages. When supplied at a high concentration (≥125 μM), guanine alleviated the toxicity of VCC234718 treatment or GuaB2 depletion via purine salvage. However, transcriptional silencing of guaB2 prevented Mtb from establishing an infection in mice, confirming that Mtb has limited access to guanine in this animal model. Together, these data provide compelling validation of GuaB2 as a new tuberculosis drug target.	Sep 2016
I04-1-Macromolecular Crystallography (fixed wavelength)	Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase Mariano M. González , Magda Kosmopoulou , Maria F. Mojica , Valerie Castillo , Philip Hinchliffe , Ilaria Pettinati , Jurgen Brem , Christopher J. Schofield , Graciela Mahler , Robert A. Bonomo , Leticia I. Llarrull , James Spencer , Alejandro J. Vila Acs Infectious Diseases 1 (11) DOI: 10.1021/acsinfecdis.5b00046 Diamond Proposal Number(s): [8922, 313] Show Abstract ▼ Abstract: Pathogenic Gram-negative bacteria resistant to almost all ?-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-?-lactamases (MBLs) produced by these bacteria inactivate most ?-lactam antibiotics, including the carbapenems, which are “last line therapies” for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of ?-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with ?-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 ?M). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.	Jul 2015

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