4DXD

Staphylococcal Aureus FtsZ in complex with 723

Summary for 4DXD

• Entry DOI: 10.2210/pdb4dxd/pdb
• Descriptor: Cell division protein FtsZ, GUANOSINE-5'-DIPHOSPHATE, 3-[(6-chloro[1,3]thiazolo[5,4-b]pyridin-2-yl)methoxy]-2,6-difluorobenzamide, ... (4 entities in total)
• Functional Keywords: rossmann fold, gtpase, gtp binding, cell cycle-inhibitor complex, cell cycle/inhibitor
• Biological source: Staphylococcus aureus
• Cellular location: Cytoplasm (By similarity): P0A031
• Total number of polymer chains: 1
• Total formula weight: 42706.63

Authors

Lu, J.,Soisson, S.M. (deposition date: 2012-02-27, release date: 2012-05-23, Last modification date: 2024-02-28)

Primary citation

Tan, C.M.,Therien, A.G.,Lu, J.,Lee, S.H.,Caron, A.,Gill, C.J.,Lebeau-Jacob, C.,Benton-Perdomo, L.,Monteiro, J.M.,Pereira, P.M.,Elsen, N.L.,Wu, J.,Deschamps, K.,Petcu, M.,Wong, S.,Daigneault, E.,Kramer, S.,Liang, L.,Maxwell, E.,Claveau, D.,Vaillancourt, J.,Skorey, K.,Tam, J.,Wang, H.,Meredith, T.C.,Sillaots, S.,Wang-Jarantow, L.,Ramtohul, Y.,Langlois, E.,Landry, F.,Reid, J.C.,Parthasarathy, G.,Sharma, S.,Baryshnikova, A.,Lumb, K.J.,Pinho, M.G.,Soisson, S.M.,Roemer, T.
Restoring methicillin-resistant Staphylococcus aureus susceptibility to beta-lactam antibiotics.
Sci Transl Med, 4:126ra35-126ra35, 2012

PubMed Abstract: Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to β-lactam antibiotics paired with β-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 β-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with β-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 Å 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 β-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 β-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.

PubMed: 22440737
DOI: 10.1126/scitranslmed.3003592

Experimental method

X-RAY DIFFRACTION (2.01 Å)