title: Patterns of pncA mutations in drug-resistant Mycobacterium tuberculosis isolated from patients in South Korea.
abstract: BACKGROUND
  Pyrazinamide (PZA), one of the most effective anti-tuberculosis drugs, becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by pyrazinamidase (PZase). PZA resistance is caused mainly by the loss of enzyme activity by mutation.
  
  
  OBJECTIVE
  To investigate the patterns of pncA mutations in PZA-resistant mycobacteria isolated from South Korean patients.
  
  
  METHODS
  Mycobacterial isolates with clinically proven drug resistance were cultured to determine susceptibility to anti-tuberculosis agents. pncA mutations were recognised by sequencing and compared with the relevant wild-type DNA sequence.
  
  
  RESULTS
  Among 108 isolates, 102 were successfully cultured and underwent drug susceptibility testing; all were multidrug-resistant (MDR). pncA mutations were found in 86 cultured isolates (85.1%): 55 (84.6%) in MDR and 31 (86.1%) in extensively drug-resistant isolates. Substitution of a single nucleotide was most common. The most frequent mutations were a deletion that caused a frameshift at nucleotide (nt) 71, a substitution at nt 403 and a substitution at nt 11. Combined, these accounted for ≈ 40% of all mutations. However, 15 samples (14.9%) with defective PZase activity showed no mutation.
  
  
  CONCLUSIONS
  pncA mutation in M. tuberculosis is a major mechanism of PZA resistance in MDR isolates from patients in South Korea. The patterns of mutation might be more scattered and diverse. DNA-based diagnosis of PZA resistance has potential for the rapid detection of drug resistance.
authors.affiliation: Department of Microbiology and Immunology, Jeju National University School of Medicine, Jeju, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: H K
authors.initials: HK
authors.lastname: Kwak
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: Y J
authors.initials: YJ
authors.lastname: Yun
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: M S
authors.initials: MS
authors.lastname: Lee
authors.forename: S Y
authors.initials: SY
authors.lastname: Min
authors.forename: S K
authors.initials: SK
authors.lastname: Park
authors.forename: H S
authors.initials: HS
authors.lastname: Kang
authors.forename: Y H
authors.initials: YH
authors.lastname: Maeng
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.forename: Y H
authors.initials: YH
authors.lastname: Kook
authors.forename: Y R
authors.initials: YR
authors.lastname: Kim
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000581:Amidohydrolases / Q000235:genetics*; D000995:Antitubercular Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D054908:Extensively Drug-Resistant Tuberculosis / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D056910:Republic of Korea / Q000453:epidemiology; D018088:Tuberculosis, Multidrug-Resistant / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011718:Pyrazinamide; C005296:pyrazinoic acid; D000581:Amidohydrolases; C487496:PncA protein, Mycobacterium tuberculosis