Journal
BIOCHIMIE
Volume 95, Issue 10, Pages 1880-1887Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2013.06.010
Keywords
FtsZ-targeting drugs; Bacterial resistance; MRSA; FtsZ polymerization; Antibacterial compounds
Categories
Funding
- TAXIS Pharmaceuticals, Inc.
- University of Medicine and Dentistry of New Jersey
- Rutgers - The State University of New Jersey
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New antibiotics with novel mechanisms of action are urgently needed to overcome the growing bacterial resistance problem faced by clinicians today. PC190723 and related compounds represent a promising new class of antibacterial compounds that target the essential bacterial cell division protein FtsZ. While this family of compounds exhibits potent antistaphylococcal activity, they have poor activity against enterococci and streptococci. The studies described herein are aimed at investigating the molecular basis of the enterococcal and streptococcal resistance to this family of compounds. We show that the poor activity of the compounds against enterococci and streptococci correlates with a correspondingly weak impact of the compounds on the self-polymerization of the FtsZ proteins from those bacteria. In addition, computational and mutational studies identify two key FtsZ residues (E34 and R308) as being important determinants of enterococcal and streptococcal resistance to the PC190723-type class of compounds. (C) 2013 Elsevier Masson SAS. All rights reserved.
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