JAC Advance Access published online on February 4, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh114
© 2004 by The British Society for Antimicrobial Chemotherapy
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original article
1 Department of Experimental
Medicine, University of L’Aquila, Coppito-67100, L’Aquila,
Italy;
* Corresponding author. E-mail: i.chopra{at}leeds.ac.uk.
Received 27 August 2003
; revised 15 December 2003
; accepted 16 December 2003
Objectives: Infections caused by Staphylococcus aureus might be treated with agents
whose primary indications are for other infections. Clofazimine,
an established anti-mycobacterial drug, could be such a candidate.
However, the anti-staphylococcal properties of clofazimine have
not been fully described and its mode of action, possibly involving
inhibition of both RNA polymerase and a membrane-located target,
has not been explored in detail. We have now conducted experiments
to address these issues. Methods: Using established procedures, we examined
the activity of clofazimine against a range of clinical isolates
of S. aureus and determined whether it was bactericidal,
exhibited a post-antibiotic effect (PAE), or interacted synergically
with other agents. The potential for emergence of clofazimine-resistant
mutants was also examined. Mode of action studies involved macromolecular
synthesis assays, cross-screening against rifampicin-resistant mutants,
susceptibility of RNA polymerase to clofazimine in vitro and
several methods to detect drug-induced membrane damage. Results: Clofazimine demonstrated good anti-staphylococcal
activity encompassing MSSA, MRSA and GISA. It was bactericidal and
resistant mutants could not be isolated. Clofazimine did not exhibit
a PAE and failed to act synergically with other drugs. No evidence
for specific inhibition of RNA polymerase was obtained. Clofazimine
caused non-specific inhibition of DNA, RNA and protein synthesis,
consistent with membrane-damaging activity that was detected in
three independent assays for membrane disrupting agents. Conclusions: Clofazimine is a potent anti-staphylococcal
agent. It appears to be a membrane-disrupting agent and does not
inhibit RNA polymerase.
Keywords: Staphylococcus aureus, mechanisms
of antibiotic action, membrane-disrupting agent
Anti-staphylococcal activity and mode of action
of clofazimine
2 Antimicrobial Research
Centre and Division of Microbiology, School of Biochemistry and
Molecular Biology, University of Leeds, Leeds LS2 9JT, UK
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. G. Hurdle, R. Yendapally, D. Sun, and R. E. Lee Evaluation of Analogs of Reutericyclin as Prospective Candidates for Treatment of Staphylococcal Skin Infections Antimicrob. Agents Chemother., September 1, 2009; 53(9): 4028 - 4031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Cholo, H. I. Boshoff, H. C. Steel, R. Cockeran, N. M. Matlola, K. J. Downing, V. Mizrahi, and R. Anderson Effects of clofazimine on potassium uptake by a Trk-deletion mutant of Mycobacterium tuberculosis J. Antimicrob. Chemother., January 1, 2006; 57(1): 79 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. O'Neill, K. Miller, B. Oliva, and I. Chopra Comparison of assays for detection of agents causing membrane damage in Staphylococcus aureus J. Antimicrob. Chemother., December 1, 2004; 54(6): 1127 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Stubbings, J. M. Bostock, E. Ingham, and I. Chopra Assessment of a microplate method for determining the post-antibiotic effect in Staphylococcus aureus and Escherichia coli J. Antimicrob. Chemother., July 1, 2004; 54(1): 139 - 143. [Abstract] [Full Text] [PDF]
|
|