Inhibition of the Sole Type I Signal Peptidase of Mycobacterium tuberculosis Is Bactericidal under Replicating and Nonreplicating Conditions

Ollinger, Juliane; O'Malley, Theresa; Ahn, Ji Yun; Odingo, Joshua; Parish, Tanya

doi:10.1128/jb.00224-12

Cited by 29 publications

(23 citation statements)

References 38 publications

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“…For many of these mutants, it was also shown that they were most strongly sensitized to inhibitors of the partially depleted protein. These and other data (Giaever et al 1999;DeVito et al 2002;Lum et al 2004;Yin et al 2004;Donald et al 2009;Abrahams et al 2012a;Ollinger et al 2012) confirmed that partial depletion of an in vitro essential protein often causes compound-specific MIC shifts and can thus provide information on the MOA of a bioactive small molecule. However, as is the case for overexpression, underexpression studies by themselves are not sufficient to claim the underproduced protein as the MIC determining target of an inhibitor, as underexpression could also decrease the MIC by sensitizing other enzymes in the same pathway to chemical inhibition.…”

Section: Linking Small Molecules To Candidate Targets By Increasing Osupporting

confidence: 66%

“…In Mtb, transcriptional repression instead of antisense RNA has been used to generate mutants expressing lower than wild-type levels of pantothenate synthase (PanC), diaminopimelate decarboxylase (LysA), isocitrate lyase (Icl1), or the type I signal peptidase (LepB). In addition, these recently constructed mutants show target-specific changes in their susceptibility to different small-molecule inhibitors (Abrahams et al 2012a;Ollinger et al 2012). WCS with these strains promises to identify new inhibitors that are able to reach the cytoplasm of Mtb and inhibit a desired target.…”

Section: Target-directed Wcsmentioning

confidence: 99%

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Genetic Approaches to Facilitate Antibacterial Drug Development

Schnappinger

2015

Cold Spring Harb Perspect Med

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Section: Linking Small Molecules To Candidate Targets By Increasing Osupporting

confidence: 66%

Section: Target-directed Wcsmentioning

confidence: 99%

Genetic Approaches to Facilitate Antibacterial Drug Development

Schnappinger

2015

Cold Spring Harb Perspect Med

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“…However, this is often prevented by transcriptional leakiness, slow or incomplete depletion of transcriptionally regulated gene products, mutations that interfere with regulation, or a combination thereof (6,7,30). Here we demonstrated that these problems can be drastically reduced or overcome entirely with a switch that combines transcriptional repression with regulated proteolysis.…”

Section: Discussionmentioning

confidence: 83%

A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence

Kim

O’Brien

Sharma

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

152

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Antibacterial drug development suffers from a paucity of targets whose inhibition kills replicating and nonreplicating bacteria. The latter include phenotypically dormant cells, known as persisters, which are tolerant to many antibiotics and often contribute to failure in the treatment of chronic infections. This is nowhere more apparent than in tuberculosis caused by Mycobacterium tuberculosis, a pathogen that tolerates many antibiotics once it ceases to replicate. We developed a strategy to identify proteins that Mycobacterium tuberculosis requires to both grow and persist and whose inhibition has the potential to prevent drug tolerance and persister formation. This strategy is based on a tunable dualcontrol genetic switch that provides a regulatory range spanning three orders of magnitude, quickly depletes proteins in both replicating and nonreplicating mycobacteria, and exhibits increased robustness to phenotypic reversion. Using this switch, we demonstrated that depletion of the nicotinamide adenine dinucleotide synthetase (NadE) rapidly killed Mycobacterium tuberculosis under conditions of standard growth and nonreplicative persistence induced by oxygen and nutrient limitation as well as during the acute and chronic phases of infection in mice. These findings establish the dual-control switch as a robust tool with which to probe the essentiality of Mycobacterium tuberculosis proteins under different conditions, including those that induce antibiotic tolerance, and NadE as a target with the potential to shorten current tuberculosis chemotherapies.

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“…Whole cell screens against this FabF-underexpressor identified platencin and platensimycin, the founding members of a new class of fatty acid biosynthesis inhibitors with broad-spectrum activity against Gram-positive bacteria (75–78). M. tuberculosis mutants expressing lower than wt levels of PanC, LysA, Icl1, or LepB have recently been constructed and also show target-specific changes in their susceptibility to different small molecule inhibitors (79, 80). Whole cell screens with these strains promise to identify new inhibitors of pantothenate synthase, diaminopimelate decarboxylase, isocitrate lyase, and the type I signal peptidase, respectively.…”

Section: Applicationsmentioning

confidence: 99%

Regulated Expression Systems for Mycobacteria and Their Applications

Schnappinger

Ehrt

2014

Microbiol Spectr

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For bacterial model organisms like Escherichia coli and Bacillus subtilis genetic tools to experimentally manipulate the activity of individual genes existed for decades. But for genetically less tractable yet medically important bacteria such as M. tuberculosis such tools have rarely been available. More recently several groups developed genetic switches that function efficiently in M. tuberculosis and other mycobacteria. Together these systems utilize six different transcription factors, eight different regulated promoters, and three different regulatory principles. Here we describe their design features, review their main applications, and discuss advantages and disadvantages of regulating transcription, translation, or protein stability for controlling gene activities in bacteria.

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Inhibition of the Sole Type I Signal Peptidase of Mycobacterium tuberculosis Is Bactericidal under Replicating and Nonreplicating Conditions

Cited by 29 publications

References 38 publications

Genetic Approaches to Facilitate Antibacterial Drug Development

Genetic Approaches to Facilitate Antibacterial Drug Development

A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence

Regulated Expression Systems for Mycobacteria and Their Applications

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