8HTB

Staphylococcus aureus FtsZ 12-316 complexed with TXH9179

8HTB の概要

• エントリーDOI: 10.2210/pdb8htb/pdb
• 分子名称: Cell division protein FtsZ, GUANOSINE-5'-DIPHOSPHATE, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: gtpase, protein-inhibitor complex, antibacterial agent, hydrolase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32681.63

構造登録者

Bryan, E.,Ferrer-Gonzalez, E.,Sagong, H.Y.,Fujita, J.,Mark, L.,Kaul, M.,LaVoie, E.J.,Matsumura, H.,Pilch, D.S. (登録日: 2022-12-21, 公開日: 2023-09-20)

主引用文献

Bryan, E.,Ferrer-Gonzalez, E.,Sagong, H.Y.,Fujita, J.,Mark, L.,Kaul, M.,LaVoie, E.J.,Matsumura, H.,Pilch, D.S.
Structural and Antibacterial Characterization of a New Benzamide FtsZ Inhibitor with Superior Bactericidal Activity and In Vivo Efficacy Against Multidrug-Resistant Staphylococcus aureus.
Acs Chem.Biol., 18:629-642, 2023

PubMed Abstract: Methicillin-resistant (MRSA) is a multidrug-resistant (MDR) bacterial pathogen of acute clinical significance. Resistance to current standard-of-care antibiotics, such as vancomycin and linezolid, among nosocomial and community-acquired MRSA clinical isolates is on the rise. This threat to global public health highlights the need to develop new antibiotics for the treatment of MRSA infections. Here, we describe a new benzamide FtsZ inhibitor (TXH9179) with superior antistaphylococcal activity relative to earlier-generation benzamides like PC190723 and TXA707. TXH9179 was found to be 4-fold more potent than TXA707 against a library of 55 methicillin-sensitive (MSSA) and MRSA clinical isolates, including MRSA isolates resistant to vancomycin and linezolid. TXH9179 was also associated with a lower frequency of resistance relative to TXA707 in all but one of the MSSA and MRSA isolates examined, with the observed resistance being due to mutations in the gene. TXH9179 induced changes in MRSA cell morphology, cell division, and FtsZ localization are fully consistent with its actions as a FtsZ inhibitor. Crystallographic studies demonstrate the direct interaction of TXH9179 with FtsZ (SaFtsZ), while delineating the key molecular contacts that drive complex formation. TXH9179 was not associated with any mammalian cytotoxicity, even at a concentration 10-fold greater than that producing antistaphylococcal activity. In serum, the carboxamide prodrug of TXH9179 (TXH1033) is rapidly hydrolyzed to TXH9179 by serum acetylcholinesterases. Significantly, both intravenously and orally administered TXH1033 exhibited enhanced in vivo efficacy relative to the carboxamide prodrug of TXA707 (TXA709) in treating a mouse model of systemic (peritonitis) MRSA infection. Viewed as a whole, our results highlight TXH9179 as a promising new benzamide FtsZ inhibitor worthy of further development.

PubMed: 36854145
DOI: 10.1021/acschembio.2c00934

実験手法

X-RAY DIFFRACTION (1.3 Å)