title: A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents.
abstract: OBJECTIVE
  Nitrofuranylamides (NFAs) are nitroaromatic compounds that have recently been discovered and have potent anti-tuberculosis (TB) activity. A foundational study was performed to evaluate whether this class of agents possesses microbiological properties suitable for future antimycobacterial therapy.
  
  
  METHODS
  Five representative compounds of the NFA series were evaluated by standard microbiological assays to determine MICs, MBCs, activity against anaerobic non-replicating persistent Mycobacterium tuberculosis, post-antibiotic effects (PAEs), antibiotic synergy and the basis for resistance.
  
  
  RESULTS
  The antimicrobial activity of these compounds was restricted to bacteria of the M. tuberculosis complex, and all compounds were highly active against drug-susceptible and -resistant strains of M. tuberculosis, with MICs 0.0004-0.05 mg/L. Moreover, no antagonism was observed with front-line anti-TB drugs. Activity was also retained against dormant bacilli in two in vitro low-oxygen models for M. tuberculosis persistence. A long PAE was observed, which was comparable to that of rifampicin, but superior to isoniazid and ethambutol. Spontaneous NFA-resistant mutants arose at a frequency of 10(-5)-10(-7), comparable to that for isoniazid (10(-5)-10(-6)). Some of these mutants exhibited cross-resistance to one or both of the nitroimidazoles PA-824 and OPC-67683. Cross-resistance was associated with inactivation of the reduced F(420)-deazaflavin cofactor pathway and not with inactivation of the Rv3547, the nitroreductase for PA-824 and OPC-67683.
  
  
  CONCLUSIONS
  Based on these studies, NFAs have many useful antimycobacterial properties applicable to TB chemotherapy and probably possess a unique mode of action that results in good activity against active and dormant M. tuberculosis. Therefore, the further development of lead compounds in this series is warranted.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Robin B
authors.initials: RB
authors.lastname: Lee
authors.forename: Nageshwar R
authors.initials: NR
authors.lastname: Budha
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Carson
authors.forename: Jianjun
authors.initials: J
authors.lastname: Qi
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Cho
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D015394:Molecular Structure; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009574:Nitro Compounds / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D009574:Nitro Compounds; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; D011084:Polycyclic Aromatic Hydrocarbons