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Genetic Strategies for Identifying New Drug Targets

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  • Authors: Andrej Trauner1, Christopher M. Sassetti2, Eric J. Rubin3
  • Editors: Graham F. Hatfull4, William R. Jacobs Jr.5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115; 2: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655; 3: Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115; 4: University of Pittsburgh, Pittsburgh, PA; 5: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
  • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0030-2013
  • Received 16 September 2013 Accepted 19 September 2013 Published 25 July 2014
  • E. J. Rubin, erubin@hsph.harvard.edu
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  • Abstract:

    Genetic strategies have yet to come into their own as tools for antibiotic development. While holding a lot of initial promise, they have only recently started to bear fruit in the quest for new drug targets. An ever-increasing body of knowledge is showing that genetics can lead to significant improvements in the success and efficiency of drug discovery. Techniques such as high-frequency transposon mutagenesis and expression modulation have matured and have been applied successfully not only to the identification and characterization of new targets, but also to their validation as tractable weaknesses of bacteria. Past experience shows that choosing targets must not rely on gene essentiality alone, but rather needs to incorporate knowledge of the system as a whole. The ability to manipulate genes and their expression is key to ensuring that we understand the entire set of processes that are affected by drug treatment. Focusing on exacerbating these perturbations, together with the identification of new targets to which resistance has not yet occurred—both enabled by genetic approaches—may point us toward the successful development of new combination therapies engineered based on underlying biology.

  • Citation: Trauner A, Sassetti C, Rubin E. 2014. Genetic Strategies for Identifying New Drug Targets. Microbiol Spectrum 2(4):MGM2-0030-2013. doi:10.1128/microbiolspec.MGM2-0030-2013.

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/content/journal/microbiolspec/10.1128/microbiolspec.MGM2-0030-2013
2014-07-25
2017-08-22

Abstract:

Genetic strategies have yet to come into their own as tools for antibiotic development. While holding a lot of initial promise, they have only recently started to bear fruit in the quest for new drug targets. An ever-increasing body of knowledge is showing that genetics can lead to significant improvements in the success and efficiency of drug discovery. Techniques such as high-frequency transposon mutagenesis and expression modulation have matured and have been applied successfully not only to the identification and characterization of new targets, but also to their validation as tractable weaknesses of bacteria. Past experience shows that choosing targets must not rely on gene essentiality alone, but rather needs to incorporate knowledge of the system as a whole. The ability to manipulate genes and their expression is key to ensuring that we understand the entire set of processes that are affected by drug treatment. Focusing on exacerbating these perturbations, together with the identification of new targets to which resistance has not yet occurred—both enabled by genetic approaches—may point us toward the successful development of new combination therapies engineered based on underlying biology.

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FIGURE 1

High-frequency transposon mutagenesis. Any gene can have multiple potential transposon insertion sites (marked with dark gray bars). Transposon insertion is usually selected for by using antibiotic markers encoded within it and on a basic level results in the disruption of gene function. Identifying the site of insertion relies on the same principle as genome sequencing. Genomic DNA is sheared and an adaptor of known sequence is ligated to the fragments. In the case of transposon insertion site scoring, the resulting pool is amplified using primers specific for the transposon (in the simplest case these are the same for both flanks of the transposon; P) and a primer specific for the adapter (P). The number of reads mapping to each genomic locus is proportional to the abundance of the strain carrying this insertion. The frequency of transposon insertion reflects gene essentiality. Genes that can tolerate insertions in multiple sites throughout their coding sequence are deemed nonessential. An organism cannot tolerate the disruption of an essential gene; therefore, no insertions can be detected. Genes that are not essential in a wild-type background under “normal” conditions but become essential once the system is suitably perturbed (e.g., low pH, presence of another mutation, drug treatment) provide a special case and are considered conditionally essential. Statistical methods should be used to determine whether a gene has a significantly low number of insertions. More elaborate transposon architectures may include the presence of transcriptional terminators (Ω) or outward-facing inducible promoters (adapted from reference 69 ). Using such systems provides greater information because transposon insertion gains additional modalities that go beyond simple gene disruption. Since the directionality of insertion carries information, it is important to be able to use different primers for each transposon flank (P, P) during insertion scoring. doi:10.1128/microbiolspec.MGM2-0030-2013.f1

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0030-2013
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FIGURE 2

Summary of genetic approaches to studying drug targets. Both forward- and reverse-genetic approaches can be used to provide overlapping and complementary tools for the investigation of antibiotic targets. The limitations and advantages are summarized in the boxes. The asterisk refers to a mutation within the promoter or coding region resulting in drug resistance. P, promoter; Tn, transposon; EMS, ethyl methanesulfonate; TF, transcription factor; MOA, mechanism of action. doi:10.1128/microbiolspec.MGM2-0030-2013.f2

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0030-2013
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