title: Resistance to first-line anti-TB drugs is associated with reduced nitric oxide susceptibility in Mycobacterium tuberculosis.
abstract: OBJECTIVE
  The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug susceptibility and clinical outcome is not known.
  
  
  METHODS
  In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO.
  
  
  RESULTS
  Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1 mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters but a tendency towards lower rate of weight gain after two months of treatment, independent of antibiotic resistance.
  
  
  CONCLUSIONS
  There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions.
authors: Division of Microbiology and Molecular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. jonna.idh@liu.se
authors: Jonna
authors: J
authors: Idh
authors: Mekidim
authors: M
authors: Mekonnen
authors: Ebba
authors: E
authors: Abate
authors: Wassihun
authors: W
authors: Wedajo
authors: Jim
authors: J
authors: Werngren
authors: Kristian
authors: K
authors: Ängeby
authors: Maria
authors: M
authors: Lerm
authors: Daniel
authors: D
authors: Elias
authors: Tommy
authors: T
authors: Sundqvist
authors: Abraham
authors: A
authors: Aseffa
authors: Olle
authors: O
authors: Stendahl
authors: Thomas
authors: T
authors: Schön
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology*; D015373:Bacterial Typing Techniques; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005002:Ethiopia; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D009569:Nitric Oxide