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Neeraj Dhar

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Publications associées (54)

Phenotypic Heterogeneity in Mycobacterium tuberculosis

John McKinney, Neeraj Dhar, Giulia Manina

The interaction between the host and the pathogen is extremely complex and is affected by anatomical, physiological, and immunological diversity in the microenvironments, leading to phenotypic diversity of the pathogen. Phenotypic heterogeneity, defined as ...

Amer Soc Microbiology2016

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

John McKinney, Neeraj Dhar, François Signorino-Gelo

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 ison ...

Elsevier Science Bv2016

Bioluminescence for Assessing Drug Potency against Nonreplicating Mycobacterium tuberculosis

Stewart Cole, Neeraj Dhar, Claudia Sala, Ruben Hartkoorn, Ming Zhang, Benoit Lechartier, Anthony Vocat

Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potenc ...

American Society for Microbiology2015

2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1

Gaëlle Séraphine Kolly, Stewart Cole, Neeraj Dhar, Florence Pojer, Ruben Hartkoorn, Joao Pedro De Almeida Neres

Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 mu M, ...

American Chemical Society2015

Stressed Mycobacteria Use the Chaperone ClpB to Sequester Irreversibly Oxidized Proteins Asymmetrically Within and Between Cells

Michaël Unser, Olivia Mariani, John McKinney, Neeraj Dhar

Mycobacterium tuberculosis (Mtb) defends itself against host immunity and chemotherapy at several levels, including the repair or degradation of irreversibly oxidized proteins (IOPs). To investigate how Mtb deals with IOPs that can neither be repaired nor ...

Cell Press2015

Whole Cell Target Engagement Identifies Novel Inhibitors of Mycobacterium tuberculosis Decaprenylphosphoryl-beta-D-ribose Oxidase

John McKinney, Neeraj Dhar

We have targeted the Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose oxidase (Mt-DprE1) for potential chemotherapeutic intervention of tuberculosis. A multicopy suppression strategy that overexpressed Mt-DprEl in M. bovis BCG was used to prof ...

Amer Chemical Soc2015

Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable beta-Lactam Antibiotic

John McKinney, Neeraj Dhar, François Signorino-Gelo

Recent clinical studies indicate that meropenem, a beta-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a ...

American Society for Microbiology2015

Stress and Host Immunity Amplify Mycobacterium tuberculosis Phenotypic Heterogeneity and Induce Nongrowing Metabolically Active Forms

John McKinney, Neeraj Dhar, Giulia Manina

Nonreplicating and metabolically quiescent bacteria are implicated in latent tuberculosis infections and relapses following "sterilizing" chemotherapy. However, evidence linking bacterial dormancy and persistence in vivo is largely inconclusive. Here we me ...

Cell Press2015

Combinations of beta-Lactam Antibiotics Currently in Clinical Trials Are Efficacious in a DHP-I-Deficient Mouse Model of Tuberculosis Infection

John McKinney, Neeraj Dhar

We report here a dehydropeptidase-deficient murine model of tuberculosis (TB) infection that is able to partially uncover the efficacy of marketed broad-spectrum beta-lactam antibiotics alone and in combination. Reductions of up to 2 log CFU in the lungs o ...

American Society for Microbiology2015

Assessing the essentiality of the decaprenyl-phospho-D-arabinofuranose pathway in Mycobacterium tuberculosis using conditional mutants

Gaëlle Séraphine Kolly, John McKinney, Stewart Cole, Neeraj Dhar, Claudia Sala, Ruben Hartkoorn

In Mycobacterium tuberculosis the decaprenyl-phospho-d-arabinofuranose (DPA) pathway is a validated target for the drugs ethambutol and benzothiazinones. To identify other potential drug targets in the pathway, we generated conditional knock-down mutants o ...

Wiley-Blackwell2014

The Phosphatidyl-myo-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo

Gaëlle Séraphine Kolly, Stewart Cole, Neeraj Dhar, Claudia Sala, Ming Zhang, Naveen Kumar

The cell envelope of Mycobacterium tuberculosis contains glycans and lipids of peculiar structure that play prominent roles in the biology and pathogenesis of tuberculosis. Consequently, the chemical structure and biosynthesis of the cell wall have been in ...

American Society for Microbiology2014

In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

Stewart Cole, Neeraj Dhar, Claudia Sala, Ming Zhang, Anthony Vocat

Oxazolidinones represent a new class of antituberculosis drugs that exert their function by inhibiting protein synthesis. Here, we compared the activities of three oxazolidinones, linezolid, PNU-100480, and AZD5847, against latent tuberculosis using a simp ...

Amer Soc Microbiology2014

EspI regulates the ESX-1 secretion system in response to ATP levels in Mycobacterium tuberculosis

Stewart Cole, Neeraj Dhar, Claudia Sala, Jeffrey Chen, Ming Zhang, Jan Lars Rybniker

The function of EspI, a 70kDa protein in Mycobacterium tuberculosis, has remained unclear. Although EspI is encoded by a gene within the esx-1 locus, in this study we clarify previous conflicting results and show that EspI is not essential for ESX-1-mediat ...

Wiley-Blackwell2014

Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism

John McKinney, Neeraj Dhar, Muhittin Emre Özdemir, Ping Lu

Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week o ...

Nature Publishing Group2014

The Phosphatidyl-myo-Inositol Mannosyltransferase PimA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo (vol 196, pg 3441, 2014)

Gaëlle Séraphine Kolly, Stewart Cole, Neeraj Dhar, Claudia Sala, Ming Zhang, Naveen Kumar

American Society for Microbiology2014

Simple and Rapid Method To Determine Antimycobacterial Potency of Compounds by Using Autoluminescent Mycobacterium tuberculosis

Neeraj Dhar, Ekaterina Gelman

A major obstacle in the process of discovery of drugs against Mycobacterium tuberculosis is its extremely slow growth rate and long generation time (similar to 20 to 24 h). Consequently, determination of MICs and minimum bactericidal concentrations (MBCs) ...

Amer Soc Microbiology2014

4-Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity

John McKinney, Neeraj Dhar, Joao Pedro De Almeida Neres, François Signorino-Gelo

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequenci ...

Amer Chemical Soc2014

Dielectrophoresis-based purification of antibiotic-treated bacterial subpopulations

Philippe Renaud, John McKinney, Neeraj Dhar, Meltem Elitas, Rodrigo Martinez Duarte

Persistence of bacteria during antibiotic therapy is a widespread phenomenon, of particular importance in refractory mycobacterial infections such as leprosy and tuberculosis. Persistence is characterized by the phenotypic tolerance of a subpopulation of b ...

Royal Soc Chemistry2014

Mycobacterium tuberculosis EspB binds phospholipids and mediates EsxA-independent virulence

Stewart Cole, Neeraj Dhar, Florence Pojer, Jeffrey Chen, Ming Zhang, Stefanie Boy-Röttger, Jan Lars Rybniker

The type-VII ESX-1 secretion apparatus, encoded by the esx-1 genetic locus, is essential for the export of EsxA and EsxB, two major virulence factors of Mycobacterium tuberculosis. ESX-1 also requires the products of the unlinked espACD operon for optimal ...

Wiley-Blackwell2013

Phenotypic Profiling of Mycobacterium tuberculosis EspA Point Mutants Reveals that Blockage of ESAT-6 and CFP-10 Secretion In Vitro Does Not Always Correlate with Attenuation of Virulence

Stewart Cole, Anna De Graff Tischler, Neeraj Dhar, Florence Pojer, Jeffrey Chen, Ming Zhang, Jan Lars Rybniker

The EspA protein of Mycobacterium tuberculosis is essential for the type VII ESX-1 protein secretion apparatus, which delivers the principal virulence factors ESAT-6 and CFP-10. In this study, site-directed mutagenesis of EspA was performed to elucidate it ...

American Society for Microbiology2013

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