A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents.
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.
Hurdle
Julian G
JG
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Lee
Robin B
RB
Budha
Nageshwar R
NR
Carson
Elizabeth I
EI
Qi
Jianjun
J
Scherman
Michael S
MS
Cho
Sang Hyun
SH
McNeil
Michael R
MR
Lenaerts
Anne J
AJ
Franzblau
Scott G
SG
Meibohm
Bernd
B
Lee
Richard E
RE
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*
D000995:Antitubercular Agents; D009574:Nitro Compounds; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; D011084:Polycyclic Aromatic Hydrocarbons