ABSTRACT
Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains of Mycobacterium tuberculosis (MTB) are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high-content imaging, we identified novel 1,2,4-oxadiazole-based compounds, which allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, MTB became even more sensitive to antituberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.
Subject(s)
Antitubercular Agents , Disease Models, Animal , Macrophages , Mycobacterium tuberculosis , Oxadiazoles , Tuberculosis , Zinc , Animals , Oxadiazoles/pharmacology , Humans , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Zinc/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice , Tuberculosis/drug therapy , Mice, Inbred C57BL , Female , Drug SynergismABSTRACT
The interactions between microbes and their hosts are among the most complex biological phenomena known today. The interaction may reach from overall beneficial interaction, as observed for most microbiome/microbiota related interactions to interaction with virulent pathogens, against which host cells have evolved sophisticated defence strategies. Among the latter, the confinement of invading pathogens in a phagosome plays a key role, which often results in the destruction of the invader, whereas some pathogens may counteract phagosomal arrest and survive by gaining access to the cytosol of the host cell. In the current review, we will discuss recent insights into this dynamic process of host-pathogen interaction, using Mycobacterium tuberculosis and related pathogenic mycobacteria as main examples.
Subject(s)
Host-Pathogen Interactions , Mycobacterium tuberculosis/pathogenicity , Phagosomes/microbiology , Tuberculosis/microbiology , Humans , PhagocytosisABSTRACT
ADP-ribosylation of proteins is crucial for fundamental cellular processes. Despite increasing examples of DNA ADP-ribosylation, the impact of this modification on DNA metabolism and cell physiology is unknown. Here, we show that the DarTG toxin-antitoxin system from enteropathogenic Escherichia coli (EPEC) catalyzes reversible ADP-ribosylation of single-stranded DNA (ssDNA). The DarT toxin recognizes specific sequence motifs. EPEC DarG abrogates DarT toxicity by two distinct mechanisms: removal of DNA ADP-ribose (ADPr) groups and DarT sequestration. Furthermore, we investigate how cells recognize and deal with DNA ADP-ribosylation. We demonstrate that DNA ADPr stalls replication and is perceived as DNA damage. Removal of ADPr from DNA requires the sequential activity of two DNA repair pathways, with RecF-mediated homologous recombination likely to transfer ADP-ribosylation from single- to double-stranded DNA (dsDNA) and subsequent nucleotide excision repair eliminating the lesion. Our work demonstrates that these DNA repair pathways prevent the genotoxic effects of DNA ADP-ribosylation.
Subject(s)
ADP-Ribosylation , DNA Repair , DNA Replication , DNA, Bacterial/metabolism , DNA-Binding Proteins/metabolism , Enteropathogenic Escherichia coli/metabolism , Escherichia coli Proteins/metabolism , Homologous Recombination , Adenosine Diphosphate Ribose/metabolism , Microbial Viability , Models, Biological , SOS Response, GeneticsABSTRACT
Stress response to fluctuating environments often implies a time-consuming reprogramming of gene expression. In bacteria, the so-called bet hedging strategy, which promotes phenotypic stochasticity within a cell population, is the only fast stress response described so far(1). Here, we show that Caulobacter crescentus asymmetrical cell division allows an immediate bimodal response to a toxic metals-rich environment by allocating specific defence strategies to morphologically and functionally distinct siblings. In this context, a motile swarmer cell favours negative chemotaxis to flee from a copper source, whereas a sessile stalked sibling engages a ready-to-use PcoAB copper homeostasis system, providing evidence of a prompt stress response through intrinsic bacterial dimorphism.
