This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Baum, E. Z.
Right arrow Articles by Bush, K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baum, E. Z.
Right arrow Articles by Bush, K.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2009, p. 3240-3247, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00166-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

MurF Inhibitors with Antibacterial Activity: Effect on Muropeptide Levels {triangledown}

Ellen Z. Baum,1* Steven M. Crespo-Carbone,1 Barbara D. Foleno,1 Lee D. Simon,2 Jerome Guillemont,3 Mark Macielag,1,{dagger} and Karen Bush1,{ddagger}

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869,1 Rutgers Food Science Electron Microscopy Facility, 65 Dudley Road, New Brunswick, New Jersey 08901,2 Pharmaceutical Research & Development, Johnson & Johnson, Campus de Maigremont-BP615, Val de Reuil Cedex F-27106, France3

Received 5 February 2009/ Returned for modification 13 March 2009/ Accepted 15 May 2009

MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 µM) and had modest activity (MICs, 8 to 16 µg/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 µg/ml), including methicillin (meticillin)-susceptible and -resistant Staphylococcus aureus isolates and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with ≥2x MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (≤1x MIC), the level of accumulation of the substrate was less pronounced (15-fold greater compared to the amount for the control). However, a 50% increase in the amount of the MurF product compared to the control was reproducibly observed, consistent with the possible upregulation of muropeptide biosynthesis upon partial inhibition of this pathway. The overexpression of cloned MurF appeared to partly alleviate the DQ1-mediated inhibition of muropeptide synthesis. The identification of MurF inhibitors such as DQ1 and DQ2 that disrupt cell wall biosynthesis suggests that MurF remains a viable target for an antibacterial agent.

* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, NJ 08869. Phone: (908)704-4320. Fax: (908)707-3501. E-mail: EBaum{at}its.jnj.com

{triangledown} Published ahead of print on 26 May 2009.

{dagger} Present address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512.

{ddagger} Present address: Biology Department, Indiana University, Bloomington, IN 47405.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3240-3247, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.00166-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»