Conjugates of plumbagin and phenyl-2-amino-1-thioglucoside inhibit MshB, a deacetylase involved in the biosynthesis of mycothiol

Gammon, David W.; Steenkamp, Daniël J.; Mavumengwana, Vuyo; Marakalala, Mohlopheni J.; Mudzunga, Theophilus T.; Hunter, Roger; Muganza, F. M.

doi:10.1016/j.bmc.2010.02.049

Cited by 30 publications

(26 citation statements)

References 40 publications

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“…Other members of the PIG-L superfamily have previously been shown to be amenable to specific inhibition by small molecule compounds (de Macedo et al, 2003;Metaferia et al, 2007;Gammon et al, 2010). Contrary to expectations, no obvious role in LPS biosynthesis could be demonstrated.…”

Section: Discussionmentioning

confidence: 77%

A putative de-N-acetylase of the PIG-L superfamily affects fluoroquinolone tolerance inPseudomonas aeruginosa

et al. 2014

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A major cause of treatment failure of infections caused by Pseudomonas aeruginosa is the presence of antibiotic-insensitive persister cells. The mechanism of persister formation in P. aeruginosa is largely unknown, and so far, only few genetic determinants have been linked to P. aeruginosa persistence. Based on a previous high-throughput screening, we here present dnpA (de-N-acetylase involved in persistence; gene locus PA14_66140/PA5002) as a new gene involved in noninherited fluoroquinolone tolerance in P. aeruginosa. Fluoroquinolone tolerance of a dnpA mutant is strongly reduced both in planktonic culture and in a biofilm model, whereas overexpression of dnpA in the wild-type strain increases the persister fraction. In addition, the susceptibility of the dnpA mutant to different classes of antibiotics is not affected. dnpA is part of the conserved LPS core oligosaccharide biosynthesis gene cluster. Based on primary sequence analysis, we predict that DnpA is a de-N-acetylase, acting on an unidentified substrate. Site-directed mutagenesis suggests that this enzymatic activity is essential for DnpA-mediated persistence. A transcriptome analysis indicates that DnpA primarily affects the expression of genes involved in surface-associated processes. We discuss the implications of these findings for future antipersister therapies targeted at chronic P. aeruginosa infections.

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Section: Discussionmentioning

confidence: 77%

A putative de-N-acetylase of the PIG-L superfamily affects fluoroquinolone tolerance inPseudomonas aeruginosa

et al. 2014

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“…Since napthoquinone derivatives were known to interact with electron transport or related biochemical reactions [327],Gammon et al utilized these moieties to create plumbagin conjugated glucopyranoside derivatives as inhibitors of mca and mshB [328]. The maximum potent inhibition of mca and mshB was observed when the plumbagin moiety was separated by 5-carbon spacer from glucopyranoside moiety [328]. However, testing of the molecule in disease models of M. tuberculosis is yet to be reported.…”

Section: Mycothiolmentioning

confidence: 99%

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

Paritala¹,

Carroll²

2013

IDDT

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The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress made in the development of inhibitors of sulfur metabolism enzymes.

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“…MSH is probably critical for survival of mycobacteria inside the oxidative environment of activated macrophages where they reside. Consequently, enzymes in the MSH biosynthetic and MSH-dependent detoxification pathways are targets for the development of antibiotics for the treatment of diseases, such as tuberculosis (5)(6)(7)(8)(9)(10).…”

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confidence: 99%

Examination of Mechanism of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Reveals Unexpected Role for Dynamic Tyrosine

Huang

Hernick

2012

Journal of Biological Chemistry

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Background: MshB is a metal-dependent deacetylase involved in mycothiol biosynthesis. Results:The reaction proceeds via a general acid-base pair mechanism and uses a dynamic Tyr that modulates substrate binding, chemistry, and product release. Conclusion:The catalytic mechanism differs from a prototypical metalloprotease mechanism. Significance: Key side chains identified in these studies can be targeted for inhibitor development.

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Conjugates of plumbagin and phenyl-2-amino-1-thioglucoside inhibit MshB, a deacetylase involved in the biosynthesis of mycothiol

Cited by 30 publications

References 40 publications

A putative de-N-acetylase of the PIG-L superfamily affects fluoroquinolone tolerance inPseudomonas aeruginosa

A putative de-N-acetylase of the PIG-L superfamily affects fluoroquinolone tolerance inPseudomonas aeruginosa

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

Examination of Mechanism of N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-α-d-glucopyranoside Deacetylase (MshB) Reveals Unexpected Role for Dynamic Tyrosine

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