Please use this identifier to cite or link to this item: https://doi.org/10.1021/acsinfecdis.6b00070
Title: Pyrazinamide resistance is caused by two distinct mechanisms: Prevention of coenzyme a depletion and loss of virulence factor synthesis
Authors: Gopal, P 
Yee, M
Sarathy, J 
Liang Low, J 
Sarathy, J.P
Kaya, F
Dartois, V
Gengenbacher, M 
Dick, T 
Keywords: acyl carrier coenzyme A
aspartate decarboxylase
benzoic acid
ciprofloxacin
coenzyme A
fatty acid synthase
isoniazid
nicotinic acid
phthiocerol dimycocerosate
polyketide synthase
pyrazinoic acid
ribosome protein
ribosome protein S1
rifampicin
streptomycin
unclassified drug
virulence factor
aspartate 4-decarboxylase
bacterial protein
carboxylyase
coenzyme A
pyrazinamide
virulence factor
antibiotic resistance
antibiotic sensitivity
Article
bacterial strain
bacterium isolation
carboxy terminal sequence
controlled study
cross resistance
frameshift mutation
in vitro study
loss of function mutation
minimum inhibitory concentration
missense mutation
mutation rate
Mycobacterium bovis BCG
Mycobacterium tuberculosis
nonhuman
point mutation
priority journal
whole genome sequencing
antibiotic resistance
biosynthesis
drug effects
genetics
human
metabolism
microbiology
Mycobacterium bovis
tuberculosis
Bacterial Proteins
Carboxy-Lyases
Coenzyme A
Drug Resistance, Bacterial
Humans
Mutation, Missense
Mycobacterium bovis
Mycobacterium tuberculosis
Polyketide Synthases
Pyrazinamide
Tuberculosis
Virulence Factors
Issue Date: 2016
Citation: Gopal, P, Yee, M, Sarathy, J, Liang Low, J, Sarathy, J.P, Kaya, F, Dartois, V, Gengenbacher, M, Dick, T (2016). Pyrazinamide resistance is caused by two distinct mechanisms: Prevention of coenzyme a depletion and loss of virulence factor synthesis. ACS Infectious Diseases 2 (9) : 616-626. ScholarBank@NUS Repository. https://doi.org/10.1021/acsinfecdis.6b00070
Abstract: Pyrazinamide (PZA) is a critical component of first-and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM). Probing for cross resistance to two structural analogs of POA, nicotinic acid and benzoic acid, showed that the analogs share the PDIM-but not the CoA-related mechanism of action with POA. We demonstrated that POA depletes CoA in wild-Type bacteria, which is prevented by mutations in panD. Sequencing 10 POA-resistant Mycobacterium tuberculosis H37Rv isolates confirmed the presence of at least 2 distinct mechanisms of resistance to the drug. The emergence of resistance through the loss of a virulence factor in vitro may explain the lack of clear molecular patterns in PZA-resistant clinical isolates, other than mutations in the prodrug-converting enzyme. The apparent interference of POA with virulence pathways may contribute to the drug's excellent in vivo efficacy compared to its modest in vitro potency. © 2016 American Chemical Society.
Source Title: ACS Infectious Diseases
URI: https://scholarbank.nus.edu.sg/handle/10635/176213
ISSN: 2373-8227
DOI: 10.1021/acsinfecdis.6b00070
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