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Neeraj Dhar

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Related publications (53)

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Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis

Paul Joseph Dyson, Stewart Cole, John McKinney, Florence Pojer, Neeraj Dhar, Joao Pedro De Almeida Neres

The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. BTZ043 targets the DprE1 catalytic component of the essential enzyme decaprenylphosphoryl-beta-D-ribofuranose-2'-epimerase, thus blocking biosynthesis of arabin ...

American Association for the Advancement of Science2012

Computational Analysis of the Mutual Constraints between Single‐Cell Growth and Division Control Models

John McKinney, Neeraj Dhar, Gaëlle Madeleine Vuaridel, Ambroise Roger Vuaridel

Three models of division control are proposed to achieve cell size homeostasis: sizer, timer, and adder. However, few published studies of division control take into account the dynamics of single‐cell growth and most assume that single‐cell growth is expo ...

2019

Division site selection linked to inherited cell surface wave troughs in mycobacteria

Georg Fantner, John McKinney, Neeraj Dhar, Adrian Pascal Nievergelt, Pascal Damian Odermatt, Haig Alexander Eskandarian, Mélanie Thérèse Marie Hannebelle, Joëlle Xiao Yuan Ven

Cell division is tightly controlled in space and time to maintain cell size and ploidy within narrow bounds. In bacteria, the canonical Minicell (Min) and nucleoid occlusion (Noc) systems together ensure that division is restricted to midcell after complet ...

2017

Mycobacterium tuberculosis EspK Has Active but Distinct Roles in the Secretion of EsxA and EspB

Neeraj Dhar

The Mycobacterium tuberculosis type-7 protein secretion system ESX-1 is a major driver of its virulence. While the functions of most ESX-1 components are characterized, many others remain poorly defined. In this study, we examined the role of EspK, an ESX- ...

American Society for Microbiology2022

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

Mechanopathology of biofilm-like Mycobacterium tuberculosis cords

Maria Gabriela Kirsch, Graham Knott, John McKinney, Neeraj Dhar, Nicolas Jean Philippe Guex, Mélanie Thérèse Marie Hannebelle, Vivek Vijay Thacker, Jessica Sordet, Kunal Sharma, Maxime Jan, Anaëlle Fabienne Dubois, Richa Mishra

Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nu ...

Cell Press2023

Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

Stewart Cole, John McKinney, Claudia Sala, Neeraj Dhar, Giulia Manina

New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in ...

American Association for the Advancement of Science2009

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

Investigating the composition and recruitment of the mycobacterial ImuA'-ImuB-DnaE2 mutasome

John McKinney, Neeraj Dhar

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded 'mycobacterial ...

Elife Sciences Publ Ltd2023

2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1

Stewart Cole, Neeraj Dhar, Florence Pojer, Ruben Hartkoorn, Gaëlle Séraphine Kolly, 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

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

Boosting with a DNA vaccine expressing ESAT-6 (DNAE6) obliterates the protection imparted by recombinant BCG (rBCGE6) against aerosol Mycobacterium tuberculosis infection in guinea pigs

Neeraj Dhar

Owing to its highly immunodominant nature and ability to induce long-lived memory immunity, ESAT-6. a prominent antigen of Mycobacterium tuberculosis, has been employed in several approaches to develop tuberculosis vaccines Here, for the first time, we com ...

2009

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

Michaël Unser, John McKinney, Neeraj Dhar, Olivia Mariani

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

Development of a repressible mycobacterial promoter system based on two transcriptional repressors

Stewart Cole, Neeraj Dhar, Claudia Sala

Tightly regulated gene expression systems represent invaluable tools for studying gene function and for the validation of drug targets in bacteria. While several regulated bacterial promoters have been characterized, few of them have been successfully used ...

Oxford University Press2010

Microbial phenotypic heterogeneity and antibiotic tolerance

John McKinney, Neeraj Dhar

Phenotypic heterogeneity, defined as metastable variation in cellular parameters generated by epigenetic mechanisms, is crucial for the persistence of bacterial populations under fluctuating selective pressures. Diversity ensures that some individuals will ...

2007

Fluorescent Benzothiazinone Analogues Efficiently and Selectively Label Dpre1 in Mycobacteria and Actinobacteria

Paul Joseph Dyson, Stewart Cole, John McKinney, Neeraj Dhar, Joao Pedro De Almeida Neres, Thierry Laroche, Jérémie Piton, Raphael Christopher Sommer, Raju Mukherjee

Benzothiazinones (BTZ) are highly potent bactericidal inhibitors of mycobacteria and the lead compound, BTZ043, and the optimized drug candidate, PBTZ169, have potential for the treatment of tuberculosis. Here, we exploited the tractability of the BTZ scaf ...

2018

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

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

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

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

An Amidase_3 domain-containing N-acetylmuramyl-L-alanine amidase is required for mycobacterial cell division

Neeraj Dhar, Ashima Bhaskar

Mycobacteria possess a multi-layered cell wall that requires extensive remodelling during cell division. We investigated the role of an amidase_3 domain-containing N-acetylmuramyl-L-alanine amidase, a peptidoglycan remodelling enzyme implicated in cell div ...

Nature Research2017

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

Stewart Cole, Neeraj Dhar, Claudia Sala, 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