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JAC Advance Access published online on August 7, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn307
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents

Julian G. Hurdle1, Robin B. Lee1, Nageshwar R. Budha1, Elizabeth I. Carson1, Jianjun Qi1, Michael S. Scherman2, Sang Hyun Cho3, Michael R. McNeil2, Anne J. Lenaerts2, Scott G. Franzblau3, Bernd Meibohm1 and Richard E. Lee1,*

1 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA 2 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA 3 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

Received 16 May 2008; returned 13 June 2008; revised 20 June 2008; accepted 3 July 2008

* Corresponding author. Tel: +1-901-448-6018; Fax: +1-901-448-6828; E-mail: relee{at}utmem.edu

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.

Key Words: M. tuberculosis , nitrofuran , nitroaromatic antibiotics , latency


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