Lee Chul-Jin, Liang Xiaofei, Chen Xin, Zeng Daina, Joo Sang Hoon, Chung Hak Suk, Barb Adam W, Swanson Shauna M, Nicholas Robert A, Li Yaoxian, Toone Eric J, Raetz Christian R H, Zhou Pei
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Chem Biol. 2011 Jan 28;18(1):38-47. doi: 10.1016/j.chembiol.2010.11.011. Epub 2010 Dec 16.
LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against gram-negative infections.
LpxC是革兰氏阴性菌脂质A生物合成途径中的一种必需酶。尽管针对LpxC的几种有前景的抗菌先导化合物对不同革兰氏阴性病原体的效力通常有很大差异，但已有相关报道。我们报告称，具有二乙炔支架的抑制剂能有效克服LpxC底物结合通道序列变异导致的耐药性。化合物结合通过与代表性的LpxC直系同源物形成复合物得以捕获，结构分析揭示了较大的构象差异，这些差异大多反映了不同LpxC直系同源物固有的分子特征，而配体诱导的结构适应性变化规模较小。这些观察结果凸显了从分子层面了解LpxC酶的固有结构特征和构象可塑性对于优化LpxC抑制剂作为抗革兰氏阴性感染的广谱抗生素的必要性。
