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Publications (3)16.1 Total impact

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    ABSTRACT: Benzothiazinones (BTZs) are a new class of sulphur containing heterocyclic compounds which target DprE1, an oxidoreductase involved in the epimerisation of decaprenyl-phosphoribose (DPR) to decaprenyl-phosphoarabinose (DPA) in the Corynebacterineae, such as Corynebacterium glutamicum and Mycobacterium tuberculosis. As a result, BTZ inhibition leads to inhibition of cell wall arabinan biosynthesis. Previous studies have demonstrated the essentiality of dprE1. In contrast, Cg-UbiA a ribosyltransferase, that catalyzes the first step of DPR biosynthesis prior to DprE1, when genetically-disrupted, produced a viable mutant, suggesting that while BTZ biochemically targets DprE1, killing also occurs through chemical synthetic lethality, presumably through the lack of decaprenyl phosphate recycling. To test this hypothesis, a derivative of BTZ, BTZ043 was examined in detail against C. glutamicum and C. glutamicum::ubiA. The wild type strain was sensitive to BTZ043; however C. glutamicum::ubiA was found to be resistant, despite possessing a functional DprE1. When the gene encoding C. glutamicum Z-decaprenyl diphosphate synthase (NCgl2203) was over-expressed in wild type C. glutamicum, resistance to BTZ043 was further increased. This data demonstrates that in presence of BTZ, the bacilli accumulate DPR and fail to recycle decaprenyl phosphate, which results in the depletion of decaprenyl phosphate and ultimately leads to cell death.
    Journal of Biological Chemistry 01/2014; · 4.65 Impact Factor
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    ABSTRACT: The development of new drugs against tuberculosis and diphtheria is focused on disrupting the biogenesis of the cell wall, the unique architecture of which confers resistance against current therapies. The enzymatic pathways involved in the synthesis of the cell wall by these pathogens are well understood but the underlying regulatory mechanisms are largely unknown. Here, we characterize IpsA, a LacI-type transcriptional regulator conserved among Mycobacteria and Corynebacteria that plays a role in the regulation of cell wall biogenesis. IpsA triggers myo-inositol formation by activating ino1, which encodes inositol-phosphate synthase. An ipsA deletion mutant of Corynebacterium glutamicum cultured on glucose displayed significantly impaired growth and presented an elongated cell morphology. Further studies revealed the absence of inositol-derived lipids in the cell wall and a complete loss of mycothiol biosynthesis. The phenotype of the C. glutamicum ipsA deletion mutant was complemented to different extend by homologs from Corynebacterium diphtheriae (dip1969) and Mycobacterium tuberculosis (rv3575), indicating the conserved function of IpsA in the pathogenic species. Additional targets of IpsA with putative functions in cell wall biogenesis were identified and IpsA was shown to bind to a conserved palindromic motif within the corresponding promoter regions. Myo-inositol was identified as an effector of IpsA, causing the dissociation of the IpsA-DNA complex in vitro. This characterization of IpsA function and of its regulon sheds light on the complex transcriptional control of cell wall biogenesis in the mycolata taxon and generates novel targets for drug development.
    BMC Biology 12/2013; 11(1):122. · 7.43 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis, the etiological agent of TB, remains the leading cause of mortality from a single infectious organism. The persistence of this human pathogen is associated with its distinctive lipid-rich cell wall structure that is highly impermeable to hydrophilic chemical drugs. This highly complex and unique structure is crucial for the growth, viability and virulence of M. tuberculosis, thus representing an attractive target for vaccine and drug development. It contains a large macromolecular structure known as the mycolyl-arabinogalactan-peptidoglycan complex, as well as phosphatidyl-myo-inositol derived glycolipids with potent immunomodulatory activity, notably lipomannan and lipoarabinomannan. These cell wall components are often the targets of effective chemotherapeutic agents against TB, such as ethambutol. This review focuses on the structural details and biosynthetic pathways of both arabinogalactan and lipoarabinomannan, as well as the effects of potent drugs on these important (lipo)polysaccharides.
    Future Microbiology 01/2012; 7(1):129-47. · 4.02 Impact Factor