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John McKinney

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Publications associées (73)

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

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

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

A problem of persistence: still more questions than answers?

John McKinney

The current antibiotic resistance crisis has led to increased pressure to prioritize strategies to tackle the issue, with a strong focus being placed on the development of novel antimicrobials. However, one major obstacle that is often overlooked is persis ...

Nature Publishing Group2013

Mechanopathology of biofilm-like Mycobacterium tuberculosis cords

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

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

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

Overlapping and essential roles for molecular and mechanical mechanisms in mycobacterial cell division

John McKinney, Georg Fantner, Pascal Damian Odermatt, Adrian Pascal Nievergelt, Mélanie Thérèse Marie Hannebelle, Haig Alexander Eskandarian

Mechanisms to control cell division are essential for cell proliferation and survival. Bacterial cell growth and division require the coordinated activity of peptidoglycan synthases and hydrolytic enzymes to maintain mechanical integrity of the cell wall. ...

2020

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

Chromosome Organization and Replisome Dynamics in Mycobacterium smegmatis

John McKinney, Isabella Santi

Subcellular organization of the bacterial nucleoid and spatiotemporal dynamics of DNA replication and segregation have been studied intensively, but the functional link between these processes remains poorly understood. Here we use quantitative time-lapse ...

American Society for Microbiology2015

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

A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria

John McKinney, Florence Pojer, Matteo Dal Peraro, Tarun Chopra, Paul Murima, Giulia Fonti

Fatty acid metabolism is an important feature of the pathogenicity of Mycobacterium tuberculosis during infection. Consumption of fatty acids requires regulation of carbon flux bifurcation between the oxidative TCA cycle and the glyoxylate shunt. In Escher ...

Nature Publishing Group2016

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

Functional characterization of a vitamin B12-dependent methylmalonyl pathway in Mycobacterium tuberculosis: implications for propionate metabolism during growth on fatty acids

John McKinney

Mycobacterium tuberculosis is predicted to subsist on alternative carbon sources during persistence within the human host. Catabolism of odd- and branched-chain fatty acids, branched-chain amino acids, and cholesterol generates propionyl-coenzyme A (CoA) a ...

American Society for Microbiology2008

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

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

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

Role of the methylcitrate cycle in propionate metabolism and detoxification in Mycobacterium smegmatis

John McKinney

Catabolism of odd-chain-length fatty acids yields acetyl-CoA and propionyl-CoA. A common pathway of propionyl-CoA metabolism in micro-organisms is the methylcitrate cycle, which includes the dedicated enzymes methylcitrate synthase (MCS), methylcitrate deh ...

2007

Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria

Kai Johnsson, Gaëlle Séraphine Kolly, Graham Knott, John McKinney, Stewart Cole, Neeraj Dhar, Monica Rengifo Gonzalez, Ruben Hartkoorn, Isabella Santi, Edina Rita Székely, François Signorino-Gelo, Jan Lars Rybniker, Anthony Vocat

There is an urgent need to discover new antitubercular agents with novel mechanisms of action in order to tackle the scourge of drug-resistant tuberculosis. Here, we report the identification of such a molecule - an AminoPYrimidine-Sulfonamide (APYS1) that ...

Wiley-Blackwell2017

Establishment and Validation of Whole-Cell Based Fluorescence Assays to Identify Anti-Mycobacterial Compounds Using the Acanthamoeba castellanii - Mycobacterium marinum Host-Pathogen System

John McKinney

Tuberculosis is considered to be one of the world's deadliest disease with 2 million deaths each year. The need for new antitubercular drugs is further exacerbated by the emergence of drug-resistance strains. Despite multiple recent efforts, the majority o ...

Public Library of Science2014

A lung-on-chip model of early Mycobacterium tuberculosis infection reveals an essential role for alveolar epithelial cells in controlling bacterial growth

John McKinney, Neeraj Dhar, Kunal Sharma, Vivek Vijay Thacker

We establish a murine lung-on-chip infection model and use time-lapse imaging to reveal the dynamics of host-Mycobacterium tuberculosis interactions at an air-liquid interface with a spatiotemporal resolution unattainable in animal models and to probe the ...

2020

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

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

Dispensability of Surfactant Proteins A and D in Immune Control of Mycobacterium tuberculosis Infection following Aerosol Challenge of Mice

John McKinney

American Society for Microbiology2011