Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity,ACS Infectious Diseases

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Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-08-06 , DOI: 10.1021/acsinfecdis.1c00317
Rajeswari Basu _{1,

2} , Nan Wang _{1,

2} , Sneha Basak _{1,

2} , Fereidoon Daryaee _{1,

2} , Mustufa Babar ₂ , Eleanor K Allen ₂ , Stephen G Walker ₃ , John D Haley ₄ , Peter J Tonge _{1,

2,

5}

Affiliation

The translation of time-dependent drug-target occupancy to extended pharmacological activity at low drug concentration depends on factors such as target vulnerability and the rate of target turnover. Previously, we demonstrated that the postantibiotic effect (PAE) caused by inhibitors of bacterial drug targets could be used to assess target vulnerability, and that high levels of target vulnerability coupled with relatively low rates of target resynthesis resulted in a strong correlation between drug-target residence time and the PAE following compound washout. Although the residence time of inhibitors on UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) in Pseudomonas aeruginosa (paLpxC) results in significant PAE, inhibitors of the equivalent enzyme in Escherichia coli (ecLpxC) do not cause a PAE. Hyperactivity of the fatty acid biosynthesis enzyme FabZ or the inclusion of sub-MIC levels of azithromycin lead to the observation of a PAE for three inhibitors of ecLpxC. FabZ hyperactivity has been shown to stabilize ecLpxC, and using mass spectrometry, we demonstrate that the appearance of a PAE can be directly linked to a 3-fold increase in the stability of ecLpxC. These studies substantiate the importance of target turnover in time-dependent drug activity.

中文翻译：

靶标周转对药物靶标停留时间转化为时间依赖性抗菌活性的影响

在低药物浓度下，时间依赖性药物靶点占有率转化为扩展药理活性取决于靶点易损性和靶点周转率等因素。此前，我们证明了由细菌药物靶标抑制剂引起的抗生素后效应（PAE）可用于评估靶标的易损性，并且高水平的靶标易损性加上相对较低的靶标再合成率导致药物-靶标之间的强相关性化合物冲洗后的停留时间和 PAE。尽管抑制剂在铜绿假单胞菌 (paLpxC) 中的 UDP-3- O -酰基- N - 乙酰氨基葡糖脱乙酰酶 (LpxC)上的停留时间导致显着的 PAE，但等效酶的抑制剂在铜绿假单胞菌(paLpxC)大肠杆菌(ecLpxC) 不会引起 PAE。脂肪酸生物合成酶 FabZ 的过度活跃或包含亚 MIC 水平的阿奇霉素导致观察到三种 ecLpxC 抑制剂的 PAE。FabZ 过度活跃已被证明可以稳定 ecLpxC，并且使用质谱法，我们证明 PAE 的出现可以直接与 ecLpxC 稳定性增加 3 倍相关。这些研究证实了目标周转在时间依赖性药物活性中的重要性。

更新日期：2021-09-10

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