2012
DOI: 10.1371/journal.ppat.1003097
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4′-Phosphopantetheinyl Transferase PptT, a New Drug Target Required for Mycobacterium tuberculosis Growth and Persistence In Vivo

Abstract: The cell envelope of Mycobacterium tuberculosis, the causative agent of tuberculosis in humans, contains lipids with unusual structures. These lipids play a key role in both virulence and resistance to the various hostile environments encountered by the bacteria during infection. They are synthesized by complex enzymatic systems, including type-I polyketide synthases and type-I and -II fatty acid synthases, which require a post-translational modification to become active. This modification consists of the cova… Show more

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Cited by 72 publications
(101 citation statements)
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“…A cKD mutant of the in vitro essential CarD revealed that M. tuberculosis depends on this transcriptional regulator for replication and persistence in mice (60). Similarly, 4′-Phosphopantetheinyl transferase PptT was shown to be required for the replication and survival of M. tuberculosis during the acute and chronic phases of infection in mice and helped validate these enzymes as a potential new drug target (56). The appearance of revertants, which are unresponsive to TetR mediated transcriptional control, can complicate the analysis of essential genes in vitro and in vivo (reference (60) and our unpublished observations).…”
Section: Applicationsmentioning
confidence: 99%
“…A cKD mutant of the in vitro essential CarD revealed that M. tuberculosis depends on this transcriptional regulator for replication and persistence in mice (60). Similarly, 4′-Phosphopantetheinyl transferase PptT was shown to be required for the replication and survival of M. tuberculosis during the acute and chronic phases of infection in mice and helped validate these enzymes as a potential new drug target (56). The appearance of revertants, which are unresponsive to TetR mediated transcriptional control, can complicate the analysis of essential genes in vitro and in vivo (reference (60) and our unpublished observations).…”
Section: Applicationsmentioning
confidence: 99%
“…For the development of antibacterials, this need was initially thought to be addressable with recombinant genetic technologies that enabled both untargeted genome-wide mutations and targeted gene deletions (2). Subsequent advances achieved conditional transcriptional silencing of genes, which allowed for the identification of targets whose functions are essential both to normal physiology of the cell and to metabolism in the context of the pathophysiology of the disease of interest (3)(4)(5)(6). Notwithstanding, such advances have failed to address that drugs act on a time scale much faster than those associated with changes in de novo transcription and that many genetic approaches only achieve narrow ranges of regulation (6,7).…”
mentioning
confidence: 99%
“…In general, less is known about PTM in bacteria as this process was originally considered to be unique to eukaryotes, with the first reports of prokaryotic protein phosphorylation reported in E. coli (Manai and Cozzone 1979) and Salmonella typhimurium (Wang and Koshland 1978) in the 1970s (reviewed in Cozzone 2009). Some studies that have focused on single proteins and have found that PTMs play a role in cell envelope integrity in M. tuberculosis (Leblanc et al 2012), fluoroquinolone resistance in S. aureus (Truong-Bolduc, Ding and Hooper 2008), and resistance to the macrolide, lincosamide and streptogramin B group of antibiotics in both Gram-positive and Gram-negative bacteria (Lambert 2005). Others have looked at PTMs in resistant communities (i.e.…”
Section: Thinking Inside the Proteome: Using High-resolution Ms To Exmentioning
confidence: 99%