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JAC Advance Access originally published online on June 27, 2008
Journal of Antimicrobial Chemotherapy 2008 62(4):713-719; doi:10.1093/jac/dkn269
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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

Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis

Mekonnen Kurabachew1, Stephen H. J. Lu1, Philipp Krastel2, Esther K. Schmitt2, Bangalore L. Suresh1, Anne Goh1, John E. Knox1, Ngai Ling Ma1, Jan Jiricek1, David Beer1, Michael Cynamon3, Frank Petersen2, Veronique Dartois1, Thomas Keller1, Thomas Dick1 and Vasan K. Sambandamurthy1,*

1 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670 2 Natural Products Unit, Novartis Institute for Biomedical Research, CH-4002 Basel, Switzerland 3 Veterans Affairs Medical Center, 800 Irving Avenue, Syracuse, NY, USA

Received 22 January 2008; returned 30 April 2008; revised 22 May 2008; accepted 2 June 2008

* Corresponding author. Present address. AstraZeneca India Pvt Ltd, Bellary Road, Hebbal, Bangalore 560024, India. Tel: +91-80-23621212; Fax: +91-80-23621214; E-mail: vasan.sambandamurthy{at}astrazeneca.com

Objectives: The aim of this study was to determine the in vitro activity of lipiarmycin against drug-resistant strains of Mycobacterium tuberculosis (MTB) and to establish the resistance mechanism of MTB against lipiarmycin using genetic approaches.

Methods: MIC values were measured against a panel of drug-resistant strains of MTB using the broth microdilution method. Spontaneous lipiarmycin-resistant mutants of MTB were tested for cross-resistance to standard anti-TB drugs, and their rpoB and rpoC genes were sequenced to identify mutations.

Results: Lipiarmycin exhibited excellent inhibitory activity against multidrug-resistant strains of MTB with MIC values of <0.1 mg/L. Sequence analysis of the rpoB and rpoC genes from spontaneous lipiarmycin-resistant mutants of MTB revealed that missense mutations in these genes caused resistance to lipiarmycin. Although both lipiarmycin and rifampicin are known to inhibit the bacterial RNA polymerase, the sites of mutation in the rpoB gene were found to be different in MTB strains resistant to these inhibitors. Whereas all six rifampicin-resistant MTB strains tested had mutation in the 81 bp hotspot region of the rpoB gene spanning codons 507–533, 16 of 18 lipiarmycin-resistant strains exhibited mutation between codons 977 and 1150. The remaining two lipiarmycin-resistant strains had mutation in the rpoC gene.

Conclusions: Lipiarmycin has excellent bactericidal activity against MTB and lacks cross-resistance to standard anti-TB drugs. Furthermore, rifampicin-resistant strains remained fully susceptible to lipiarmycin, and none of the lipiarmycin-resistant MTB strains became resistant to rifampicin, highlighting the lack of cross-resistance.

Keywords: antimycobacterial activity , resistance mechanism , transcription


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