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Reverse Engineering and Synthetic Pe...

Hall, Matthew Robert,

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Reverse Engineering and Synthetic Perturbation of the Transcriptional Regulatory Network of Streptococcus pneumoniae to Identify Routes to Antibiotic Potentiation /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Reverse Engineering and Synthetic Perturbation of the Transcriptional Regulatory Network of Streptococcus pneumoniae to Identify Routes to Antibiotic Potentiation // Matthew Robert Hall.
Author:	Hall, Matthew Robert,
Description:	1 electronic resource (188 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
Contained By:	Dissertations Abstracts International86-11B.
Subject:	Biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31932713
ISBN:	9798315713401

Reverse Engineering and Synthetic Perturbation of the Transcriptional Regulatory Network of Streptococcus pneumoniae to Identify Routes to Antibiotic Potentiation /
Hall, Matthew Robert,

Reverse Engineering and Synthetic Perturbation of the Transcriptional Regulatory Network of Streptococcus pneumoniae to Identify Routes to Antibiotic Potentiation /Matthew Robert Hall. - 1 electronic resource (188 pages)

Source: Dissertations Abstracts International, Volume: 86-11, Section: B.

Streptococcus pneumoniae is a bacterial pathogen responsible for over 1 million deaths annually, with 30% of pneumococcal infections in the United States resistant to one or more antibiotics. Here, we characterize the Transcriptional Regulatory Network (TRN) of S. pneumoniae strain TIGR4 to understand the regulatory logic of this pathogen and identify strategies for enhancing antibiotic efficacy. We constructed 89 Transcription Factor Induction (TFI) strains, each of which overexpresses a barcoded and HA-tagged transcription factor in response to IPTG. Through a combination of RNAseq, an ensemble of network inference methods, and both in vivo and computational motif discovery, we reverse engineered the most comprehensive TRN for S. pneumoniae to date, comprised of 3,946 interactions between 88 transcription factors and 1,607 target genes. Transcriptional Regulator Induced Phenotype (TRIP) screens quantify relative fitness values between TFI strains and identify transcriptional pathways critical to metabolism, oxidative stress, zinc intoxication and antibiotic stress. Overexpression of three metabolic regulators, CpsR, SusR and TreR, increase resistance to the cell wall synthesis inhibitors Ceftriaxone and Vancomycin while potentiating the effects of Kanamycin and Levofloxacin. Metal and redox-regulated transcription factors were frequent TRIP hits and are best exemplified by RitR, the redox-sensitive master regulator of metal ion homeostasis, protease activity and the oxidative stress response. The apparent link between metal ions and oxidative stress led to the identification of zinc as a potentiator of both Kanamycin and Ceftriaxone. Time-kill assay-adapted TRIP screens identified proteostasis as a primary determinant of antibiotic tolerance. Overexpression of the Clp protease repressor CtsR enhanced tolerance, while overexpression of CodY reduced it, an effect reversed by branched-chain amino acid supplementation. This work provides the first comprehensive TRN of S. pneumoniae to understand its physiology and identify drug targets, while insights from TRIP screens reveal strategies to potentiate antibiotic treatment of this critical pathogen.

English

ISBN: 9798315713401Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Antibiotic resistance

Reverse Engineering and Synthetic Perturbation of the Transcriptional Regulatory Network of Streptococcus pneumoniae to Identify Routes to Antibiotic Potentiation /
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520 $a Streptococcus pneumoniae is a bacterial pathogen responsible for over 1 million deaths annually, with 30% of pneumococcal infections in the United States resistant to one or more antibiotics. Here, we characterize the Transcriptional Regulatory Network (TRN) of S. pneumoniae strain TIGR4 to understand the regulatory logic of this pathogen and identify strategies for enhancing antibiotic efficacy. We constructed 89 Transcription Factor Induction (TFI) strains, each of which overexpresses a barcoded and HA-tagged transcription factor in response to IPTG. Through a combination of RNAseq, an ensemble of network inference methods, and both in vivo and computational motif discovery, we reverse engineered the most comprehensive TRN for S. pneumoniae to date, comprised of 3,946 interactions between 88 transcription factors and 1,607 target genes. Transcriptional Regulator Induced Phenotype (TRIP) screens quantify relative fitness values between TFI strains and identify transcriptional pathways critical to metabolism, oxidative stress, zinc intoxication and antibiotic stress. Overexpression of three metabolic regulators, CpsR, SusR and TreR, increase resistance to the cell wall synthesis inhibitors Ceftriaxone and Vancomycin while potentiating the effects of Kanamycin and Levofloxacin. Metal and redox-regulated transcription factors were frequent TRIP hits and are best exemplified by RitR, the redox-sensitive master regulator of metal ion homeostasis, protease activity and the oxidative stress response. The apparent link between metal ions and oxidative stress led to the identification of zinc as a potentiator of both Kanamycin and Ceftriaxone. Time-kill assay-adapted TRIP screens identified proteostasis as a primary determinant of antibiotic tolerance. Overexpression of the Clp protease repressor CtsR enhanced tolerance, while overexpression of CodY reduced it, an effect reversed by branched-chain amino acid supplementation. This work provides the first comprehensive TRN of S. pneumoniae to understand its physiology and identify drug targets, while insights from TRIP screens reveal strategies to potentiate antibiotic treatment of this critical pathogen.
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