In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 16, No. 11 ( 2020-11-30), p. e1009063-
Abstract:
Genomic dissection of antibiotic resistance in bacterial pathogens has largely focused on genetic changes conferring growth above a single critical concentration of drug. However, reduced susceptibility to antibiotics—even below this breakpoint—is associated with poor treatment outcomes in the clinic, including in tuberculosis. Clinical strains of Mycobacterium tuberculosis exhibit extensive quantitative variation in antibiotic susceptibility but the genetic basis behind this spectrum of drug susceptibility remains ill-defined. Through a genome wide association study, we show that non-synonymous mutations in dnaA , which encodes an essential and highly conserved regulator of DNA replication, are associated with drug resistance in clinical M . tuberculosis strains. We demonstrate that these dnaA mutations specifically enhance M . tuberculosis survival during isoniazid treatment via reduced expression of katG , the activator of isoniazid. To identify DnaA interactors relevant to this phenotype, we perform the first genome-wide biochemical mapping of DnaA binding sites in mycobacteria which reveals a DnaA interaction site that is the target of recurrent mutation in clinical strains. Reconstructing clinically prevalent mutations in this DnaA interaction site reproduces the phenotypes of dnaA mutants, suggesting that clinical strains of M . tuberculosis have evolved mutations in a previously uncharacterized DnaA pathway that quantitatively increases resistance to the key first-line antibiotic isoniazid. Discovering genetic mechanisms that reduce drug susceptibility and support the evolution of high-level drug resistance will guide development of biomarkers capable of prospectively identifying patients at risk of treatment failure in the clinic.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009063
DOI:
10.1371/journal.ppat.1009063.g001
DOI:
10.1371/journal.ppat.1009063.g002
DOI:
10.1371/journal.ppat.1009063.g003
DOI:
10.1371/journal.ppat.1009063.g004
DOI:
10.1371/journal.ppat.1009063.g005
DOI:
10.1371/journal.ppat.1009063.s001
DOI:
10.1371/journal.ppat.1009063.s002
DOI:
10.1371/journal.ppat.1009063.s003
DOI:
10.1371/journal.ppat.1009063.s004
DOI:
10.1371/journal.ppat.1009063.s005
DOI:
10.1371/journal.ppat.1009063.s006
DOI:
10.1371/journal.ppat.1009063.s007
DOI:
10.1371/journal.ppat.1009063.s008
DOI:
10.1371/journal.ppat.1009063.s009
DOI:
10.1371/journal.ppat.1009063.s010
DOI:
10.1371/journal.ppat.1009063.s011
DOI:
10.1371/journal.ppat.1009063.s012
DOI:
10.1371/journal.ppat.1009063.s013
DOI:
10.1371/journal.ppat.1009063.s014
DOI:
10.1371/journal.ppat.1009063.s015
DOI:
10.1371/journal.ppat.1009063.s016
DOI:
10.1371/journal.ppat.1009063.s017
DOI:
10.1371/journal.ppat.1009063.s018
DOI:
10.1371/journal.ppat.1009063.s019
DOI:
10.1371/journal.ppat.1009063.s020
DOI:
10.1371/journal.ppat.1009063.s021
DOI:
10.1371/journal.ppat.1009063.s022
DOI:
10.1371/journal.ppat.1009063.s023
DOI:
10.1371/journal.ppat.1009063.s024
DOI:
10.1371/journal.ppat.1009063.s025
DOI:
10.1371/journal.ppat.1009063.s026
DOI:
10.1371/journal.ppat.1009063.s027
DOI:
10.1371/journal.ppat.1009063.s028
DOI:
10.1371/journal.ppat.1009063.s029
DOI:
10.1371/journal.ppat.1009063.r001
DOI:
10.1371/journal.ppat.1009063.r002
DOI:
10.1371/journal.ppat.1009063.r003
DOI:
10.1371/journal.ppat.1009063.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2205412-1
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