Publications by authors named "Esther Perez-Herran"

21 Publications

  • Page 1 of 1

Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in .

ACS Infect Dis 2021 01 15;7(1):141-152. Epub 2020 Dec 15.

Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York 10065, United States.

MmpL3, an essential mycolate transporter in the inner membrane of (), has been identified as a target of multiple, chemically diverse antitubercular drugs. However, several of these molecules seem to have secondary targets and inhibit bacterial growth by more than one mechanism. Here, we describe a cell-based assay that utilizes two-way regulation of MmpL3 expression to readily identify MmpL3-specific inhibitors. We successfully used this assay to identify a novel guanidine-based MmpL3 inhibitor from a library of 220 compounds that inhibit growth of by largely unknown mechanisms. We furthermore identified inhibitors of cytochrome - oxidase as one class of off-target hits in whole-cell screens for MmpL3 inhibitors and report a novel sulfanylacetamide as a potential QcrB inhibitor.
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http://dx.doi.org/10.1021/acsinfecdis.0c00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802072PMC
January 2021

Inhibiting the stringent response blocks entry into quiescence and reduces persistence.

Sci Adv 2019 03 20;5(3):eaav2104. Epub 2019 Mar 20.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The stringent response enables () to shut down its replication and metabolism under various stresses. Here we show that lacking the stringent response enzyme Rel was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved -deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of Rel and showed that the lead compound X9 was able to directly kill nutrient-starved and enhanced the killing activity of isoniazid. Inhibition of Rel is a promising approach to target persisters, with the potential to shorten the duration of TB treatment.
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http://dx.doi.org/10.1126/sciadv.aav2104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426458PMC
March 2019

Mycobacterial Aminoglycoside Acetyltransferases: A Little of Drug Resistance, and a Lot of Other Roles.

Front Microbiol 2019 30;10:46. Epub 2019 Jan 30.

Departamento de Microbiología, Facultad de Medicina - Instituto Universitario de Investigación de Biocomputación y Física de Sistemas Complejos, Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, Zaragoza, Spain.

Aminoglycoside acetyltransferases are important determinants of resistance to aminoglycoside antibiotics in most bacterial genera. In mycobacteria, however, aminoglycoside acetyltransferases contribute only partially to aminoglycoside susceptibility since they are related with low level resistance to these antibiotics (while high level aminoglycoside resistance is due to mutations in the ribosome). Instead, aminoglycoside acetyltransferases contribute to other bacterial functions, and this can explain its widespread presence along species of genus . This review is focused on two mycobacterial aminoglycoside acetyltransferase enzymes. First, the aminoglycoside 2'--acetyltransferase [AAC(2')], which was identified as a determinant of weak aminoglycoside resistance in , and later found to be widespread in most mycobacterial species; AAC(2') enzymes have been associated with resistance to cell wall degradative enzymes, and bactericidal mode of action of aminoglycosides. Second, the Eis aminoglycoside acetyltransferase, which was identified originally as a virulence determinant in (enhanced intracellular survival); Eis protein in fact controls production of pro-inflammatory cytokines and other pathways. The relation of Eis with aminoglycoside susceptibility was found after the years, and reaches clinical significance only in isolates resistant to the second-line drug kanamycin. Given the role of AAC(2') and Eis proteins in mycobacterial biology, inhibitory molecules have been identified, more abundantly in case of Eis. In conclusion, AAC(2') and Eis have evolved from a marginal role as potential drug resistance mechanisms into a promising future as drug targets.
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http://dx.doi.org/10.3389/fmicb.2019.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363676PMC
January 2019

Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis.

J Med Chem 2018 12 12;61(24):11327-11340. Epub 2018 Dec 12.

GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa 2 , 28760 Tres Cantos , Madrid , Spain.

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01533DOI Listing
December 2018

Identification and characterization of aspartyl-tRNA synthetase inhibitors against Mycobacterium tuberculosis by an integrated whole-cell target-based approach.

Sci Rep 2018 08 23;8(1):12664. Epub 2018 Aug 23.

School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Mycobacterium tuberculosis, the causative agent of tuberculosis, has surpassed HIV as the leading cause of death due to an infectious disease worldwide, being responsible for more than 1.5 million deaths in low-income countries. In response to a pandemic threat by drug resistant strains, the tuberculosis research community is searching for new chemical entities with novel mechanisms of action to avoid drug resistance and shorten treatment regimens using combinatorial chemotherapy. Herein, we have identified several novel chemical scaffolds, GSK97C (spiro-oxazolidin-2-one), GSK93A (2-amino-1,3-thiazole, GSK85A and GSK92A (enamides), which target M. tuberculosis aspartyl-tRNA synthetase (Mt-AspRS), an essential component of the protein synthesis machinery of tuberculosis, using a whole-cell target-based screening strategy against a genetically modified Mycobacterium bovis BCG strain. We also provide further evidence of protein inhibition and inhibitor profiling through a classical aminoacylation reaction and a tRNA-independent assay, respectively. Altogether, our results have identified a number of hit new molecules with novel mechanism of action for further development through medicinal chemistry as hits and leads.
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http://dx.doi.org/10.1038/s41598-018-31157-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107548PMC
August 2018

Synthesis, antimycobacterial activity and influence on mycobacterial InhA and PknB of 12-membered cyclodepsipeptides.

Bioorg Med Chem 2018 07 22;26(12):3166-3190. Epub 2018 Apr 22.

Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. Electronic address:

In recent years, several small natural cyclopeptides and cyclodepsipeptides were reported to have antimycobacterial activity. Following this lead, a synthetic pathway was developed for a small series of 12-membered ring compounds with one amide and two ester bonds (cyclotridepsipeptides). Within the series, the ring system proved to be necessary for growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis in the low micromolar range. Open-chain precursors and analogues were inactive. The compounds modulated autophosphorylation of the mycobacterial protein kinase B (PknB). PknB inhibitors were active at µM concentration against mycobacteria while inducers were inactive. PknB regulates the activity of the mycobacterial reductase InhA, the target of isoniazid. The activity of the series against Mycobacterium bovis BCG InhA overexpressing strains was indistinguishable from that of the parental strain suggesting that they do not inhibit InhA. All substances were not cytotoxic (HeLa > 5 µg/ml) and did not show any significant antiproliferative effect (HUVEC > 5 µg/ml; K-562 > 5 µg/ml). Within the scope of this study, the molecular target of this new type of small cyclodepsipeptide was not identified, but the data suggest interaction with PknB or other kinases may partly cause the activity.
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http://dx.doi.org/10.1016/j.bmc.2018.04.045DOI Listing
July 2018

Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656).

J Med Chem 2017 10 27;60(19):8011-8026. Epub 2017 Sep 27.

Anacor Pharmaceuticals, Inc. , 1020 E. Meadow Circle, Palo Alto, California 94303, United States.

There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC = 0.20 μM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 μM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC of >300 μM and 132 μM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00631DOI Listing
October 2017

Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.

Sci Rep 2017 08 25;7(1):9430. Epub 2017 Aug 25.

Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets.
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http://dx.doi.org/10.1038/s41598-017-09642-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573416PMC
August 2017

Detection of a Putative TetR-Like Gene Related to BCG Growth in Cholesterol Using a -Transposon Mutagenesis System.

Front Microbiol 2017 6;8:315. Epub 2017 Mar 6.

Departamento de Medicina Preventiva, Universidad Autónoma Madrid, Spain.

transposition is a powerful genetic tool for identifying mycobacterial virulence genes and studying virulence factors in relation to the host. Transposon shuttle mutagenesis is a method for constructing stable insertions in the genome of different microorganisms including mycobacteria. Using an IS derivative, we have constructed the Tn, a transposon containing a promoterless green fluorescent protein () gene. This transposon was able to transpose randomly in BCG. Bacteria with a single copy of the gene per chromosome from an BCG::Tngfp library were analyzed and cells exhibiting high levels of fluorescence were detected by flow cytometry. Application of this approach allowed for the selection of a mutant, BCG_2177c::Tn (BCG-Tn), on the basis of high level of long-standing fluorescence at stationary phase. This BCG-Tn mutant showed some particular phenotypic features compared to the wild type strain, mainly during stationary phase, when cholesterol was used as a sole carbon source, thus supporting the relationships of the targeted gene with the regulation of cholesterol metabolism in this bacteria. This approach showed that Tn is a potentially useful tool for studying the involvement of the targeted loci in metabolic pathways of mycobacteria.
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http://dx.doi.org/10.3389/fmicb.2017.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337628PMC
March 2017

Whole Cell Target Engagement Identifies Novel Inhibitors of Mycobacterium tuberculosis Decaprenylphosphoryl-β-d-ribose Oxidase.

ACS Infect Dis 2015 Dec 25;1(12):615-26. Epub 2015 Aug 25.

School of Biosciences, University of Birmingham , Birmingham B15 2TT, United Kingdom.

We have targeted the Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose oxidase (Mt-DprE1) for potential chemotherapeutic intervention of tuberculosis. A multicopy suppression strategy that overexpressed Mt-DprE1 in M. bovis BCG was used to profile the publically available GlaxoSmithKline antimycobacterial compound set, and one compound (GSK710) was identified that showed an 8-fold higher minimum inhibitory concentration relative to the control strain. Analogues of GSK710 show a clear relationship between whole cell potency and in vitro activity using an enzymatic assay employing recombinant Mt-DprE1, with binding affinity measured by fluorescence quenching of the flavin cofactor of the enzyme. M. bovis BCG spontaneous resistant mutants to GSK710 and a closely related analogue were isolated and sequencing of ten such mutants revealed a single point mutation at two sites, E221Q or G248S within DprE1, providing further evidence that DprE1 is the main target of these compounds. Finally, time-lapse microscopy experiments showed that exposure of M. tuberculosis to a compound of this series arrests bacterial growth rapidly followed by a slower cytolysis phase.
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http://dx.doi.org/10.1021/acsinfecdis.5b00065DOI Listing
December 2015

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.

Antimicrob Agents Chemother 2016 10 23;60(10):6271-80. Epub 2016 Sep 23.

Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.
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http://dx.doi.org/10.1128/AAC.01339-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038265PMC
October 2016

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.

EBioMedicine 2016 Jun 8;8:291-301. Epub 2016 May 8.

Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain. Electronic address:

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.
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http://dx.doi.org/10.1016/j.ebiom.2016.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919555PMC
June 2016

N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity.

ChemMedChem 2016 Apr 2;11(7):687-701. Epub 2016 Mar 2.

Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.

Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.
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http://dx.doi.org/10.1002/cmdc.201600020DOI Listing
April 2016

New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold.

Eur J Med Chem 2016 Apr 8;112:252-257. Epub 2016 Feb 8.

University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. Electronic address:

Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.008DOI Listing
April 2016

Antimicrobial susceptibility testing for Mycobacterium sp.

Methods Mol Biol 2015 ;1285:257-68

Diseases of the Developing World, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid, 28760, Spain.

The concept of antimicrobial susceptibility testing is an essential part of clinical microbiology. Antimicrobial testing has played a central role in the identification of new antibiotics and defining their clinical uses. Here we describe different approaches to determine the activity of compounds in medium- or high-throughput format.
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http://dx.doi.org/10.1007/978-1-4939-2450-9_15DOI Listing
December 2015

Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs.

Antimicrob Agents Chemother 2015 Apr 12;59(4):1868-75. Epub 2015 Jan 12.

Diseases of the Developing World, GSK, Severo Ochoa 2, Tres Cantos, Madrid, Spain.

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.
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http://dx.doi.org/10.1128/AAC.03913-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356839PMC
April 2015

Pulmonary Mycobacterium bovis BCG vaccination confers dose-dependent superior protection compared to that of subcutaneous vaccination.

Clin Vaccine Immunol 2014 Apr 5;21(4):594-7. Epub 2014 Feb 5.

Grupo de Genética de Micobacterias, Departmento de Microbiología, Medicina Preventiva y Salud Pública, Faculty of Medicine, Universidad de Zaragoza, Zaragoza, Spain.

Worldwide, the Mycobacterium bovis BCG vaccine is one of the most widely used vaccines. However, it appears to be ineffective in preventing pulmonary tuberculosis. Here, we show that pulmonary BCG vaccination of mice with a broad dose range provides superior protection against Mycobacterium tuberculosis challenge compared to that of subcutaneous vaccination.
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http://dx.doi.org/10.1128/CVI.00700-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993116PMC
April 2014

Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.

J Med Chem 2014 Feb 5;57(4):1276-88. Epub 2014 Feb 5.

ELT Boston, Platform Technology & Science, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.

Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.
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http://dx.doi.org/10.1021/jm401326jDOI Listing
February 2014

Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3.

PLoS One 2013 17;8(4):e60933. Epub 2013 Apr 17.

Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060933PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629081PMC
November 2013

Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis.

ChemMedChem 2013 Feb 10;8(2):313-21. Epub 2013 Jan 10.

Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline (GSK), Severo Ochoa 2, Tres Cantos, Madrid, Spain.

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.
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http://dx.doi.org/10.1002/cmdc.201200428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743164PMC
February 2013

4-Substituted thioquinolines and thiazoloquinolines: potent, selective, and Tween-80 in vitro dependent families of antitubercular agents with moderate in vivo activity.

ChemMedChem 2011 Dec 16;6(12):2252-63. Epub 2011 Sep 16.

Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus (TCMDC), GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos Madrid, Spain.

Two new families of closely related selective, non-cytotoxic, and potent antitubercular agents were discovered: thioquinolines and thiazoloquinolines. The compounds were found to possess potent antitubercular properties in vitro, an activity that is dependent on experimental conditions of MIC determination (resazurin test and the presence or absence of Tween-80). To clarify the therapeutic potential of these compound families, a medicinal chemistry effort was undertaken to generate a lead-like structure that would enable murine efficacy studies and help elucidate the in vivo implications of the in vitro observations. Although the final compounds showed only limited levels of systemic exposure in mice, modest levels of efficacy in vivo at nontoxic doses were observed.
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http://dx.doi.org/10.1002/cmdc.201100309DOI Listing
December 2011