4DXD: Staphylococcal Aureus Ftsz In Complex With 723

Citation:
Abstract
Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to beta-lactam antibiotics paired with beta-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as beta-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with beta-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 A crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the beta-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to beta-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections.
PDB ID: 4DXDDownload
MMDB ID: 99924
PDB Deposition Date: 2012/2/27
Updated in MMDB: 2012/05
Experimental Method:
x-ray diffraction
Resolution: 2.01  Å
Source Organism:
Similar Structures:
Biological Unit for 4DXD: monomeric; determined by author and by software (PISA)
Molecular Components in 4DXD
Label Count Molecule
Protein (1 molecule)
1
Cell Division Protein Ftsz
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.