A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents

Julian G. Hurdle, Robin B. Lee, Nageshwar R. Budha, Elizabeth I. Carson, Jianjun Qi, Michael S. Scherman, Sang Hyun Cho, Michael R. McNeil, Anne J. Lenaerts, Scott G. Franzblau, Bernd Meibohm, Richard E. Lee

Research output: Contribution to journalArticle

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Abstract

Objectives: 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 F420-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.

Original languageEnglish (US)
Pages (from-to)1037-1045
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume62
Issue number5
DOIs
StatePublished - Nov 1 2008

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Mycobacterium tuberculosis
Tuberculosis
Isoniazid
Anti-Bacterial Agents
Nitroreductases
Nitroimidazoles
Ethambutol
Rifampin
Pharmaceutical Preparations
Bacillus
Oxygen
Bacteria
Drug Therapy
OPC-67683
2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Hurdle, J. G., Lee, R. B., Budha, N. R., Carson, E. I., Qi, J., Scherman, M. S., ... Lee, R. E. (2008). A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents. Journal of Antimicrobial Chemotherapy, 62(5), 1037-1045. https://doi.org/10.1093/jac/dkn307

A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents. / Hurdle, Julian G.; Lee, Robin B.; Budha, Nageshwar R.; Carson, Elizabeth I.; Qi, Jianjun; Scherman, Michael S.; Cho, Sang Hyun; McNeil, Michael R.; Lenaerts, Anne J.; Franzblau, Scott G.; Meibohm, Bernd; Lee, Richard E.

In: Journal of Antimicrobial Chemotherapy, Vol. 62, No. 5, 01.11.2008, p. 1037-1045.

Research output: Contribution to journalArticle

Hurdle, JG, Lee, RB, Budha, NR, Carson, EI, Qi, J, Scherman, MS, Cho, SH, McNeil, MR, Lenaerts, AJ, Franzblau, SG, Meibohm, B & Lee, RE 2008, 'A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents', Journal of Antimicrobial Chemotherapy, vol. 62, no. 5, pp. 1037-1045. https://doi.org/10.1093/jac/dkn307
Hurdle, Julian G. ; Lee, Robin B. ; Budha, Nageshwar R. ; Carson, Elizabeth I. ; Qi, Jianjun ; Scherman, Michael S. ; Cho, Sang Hyun ; McNeil, Michael R. ; Lenaerts, Anne J. ; Franzblau, Scott G. ; Meibohm, Bernd ; Lee, Richard E. / A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents. In: Journal of Antimicrobial Chemotherapy. 2008 ; Vol. 62, No. 5. pp. 1037-1045.
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AU - Scherman, Michael S.

AU - Cho, Sang Hyun

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