UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.

UDP-3- O-（R -3-羟酰基）-N-乙酰氨基葡糖脱乙酰酶（LpxC）是催化革兰氏阴性细菌中脂质A生物合成的第一步的锌金属酶，已成为许多抗菌药物发现的目标年份。所有达到晚期临床前阶段和临床1期的抑制剂化学型均包含末端异羟肟酸，而且由于部分安全性考虑因素（包括血液动力学效应），均未成功进展。我们假设通过用不同的锌结合基团取代末端异羟肟酸可以提高LpxC抑制剂的安全性。选择N之后-羟基甲酰胺锌结合基团，我们研究了铜绿假单胞菌和大肠杆菌LpxC结合亲和力，体外抗菌效能和药理特性方面抑制剂支架各部分的构效关系。我们确定了一种新型的增强LpxC抑制剂的疏水结合作用。我们证明了一种化合物在中性粒细胞减少性小鼠大肠杆菌中的体内功效感染模型。另一种化合物在大鼠血流动力学测定中进行了测试，发现具有降压作用。该结果表明，用不同的锌结合基团取代末端异羟肟酸不足以避免以前认识到的LpxC抑制剂的安全性问题。