# Mechanism of Slow Onset Enzyme Inhibition and Translation to Time-Dependent Drug Activity

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $326,975

## Abstract

Many drug candidates fail in clinical trials due to poor in vivo efficacy in humans. We speculate
that our poor success rate at predicting in vivo drug efficacy stems from a reliance on in vitro
assessments of drug activity that are performed at constant drug concentration (under equilibrium
conditions), when in fact drug concentration is not constant in the human body. We thus propose
that the kinetics of drug-target complex formation and breakdown is a critical factor in modulating
drug action. In this proposal we will elucidate the molecular factors that dictate the impact of drug-
target residence time on in vivo drug activity. These studies will focus on inhibitors of FabI, an
enzyme drug-target from Mycobacterium tuberculosis, and LpxC, an enzyme drug target from
Gram negative ESKAPE pathogens. We will quantitate the role that intracellular events such as
target (re)synthesis, target degradation and target vulnerability have on the correlation between
drug-target residence time and antibacterial activity determined as a function of drug
concentration. This includes the prolongation of antibacterial activity following removal of drug
from the system (the post-antibiotic effect). We will develop structure-kinetics relationships for
the time-dependent inhibition of FabI and LpxC using a combination of structural and
computational biology coupled with enzyme kinetics, and synthesize inhibitors of FabI and LpxC
with extended target engagement. A mathematical model will be used that links drug-target
kinetics and drug pharmacokinetics with predictions of antibacterial activity in whole cells and
animal models of infection. Improved ability to predict in vivo drug action from in vitro parameters
will have a dramatic impact on the discovery of new therapeutic agents.

## Key facts

- **NIH application ID:** 9896835
- **Project number:** 5R01GM102864-07
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** PETER J TONGE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,975
- **Award type:** 5
- **Project period:** 2012-09-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896835

## Citation

> US National Institutes of Health, RePORTER application 9896835, Mechanism of Slow Onset Enzyme Inhibition and Translation to Time-Dependent Drug Activity (5R01GM102864-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896835. Licensed CC0.

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