Journal
ACS INFECTIOUS DISEASES
Volume 7, Issue 9, Pages 2755-2763Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00317
Keywords
Target vulnerability; LpxC; residence time; postantibiotic effect; target turnover
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Funding
- NIH [GM102864]
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The translation of time-dependent drug-target occupancy to extended pharmacological activity at low drug concentration relies on factors such as target vulnerability and target turnover rate. The study demonstrated a strong correlation between drug-target residence time and postantibiotic effect (PAE) following compound washout, with high target vulnerability and low target resynthesis leading to increased PAE. Moreover, hyperactivity of the fatty acid biosynthesis enzyme FabZ or sub-MIC levels of azithromycin can induce PAE by stabilizing the target enzyme ecLpxC.
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.
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