Drug Target Residence Time and the Pharmacodynamics of Antibacterial Agents

Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity

“…9,10,28−33 In our efforts to delineate the factors that underly the implementation of kinetic selectivity, we identified target vulnerability and target turnover as critical factors in modulating the translation of extended target occupancy to prolonged drug activity. 7,8 In antibacterial space, time-dependent drug activity can be assessed using the postantibiotic effect (PAE), which is the delay in bacterial growth following compound washout. 34 While several mechanisms can be responsible for the PAE, we previously described correlations between drug-target residence time and PAE demonstrating that the ribosome and the LpxC enzyme from P. aeruginosa were highly vulnerable targets in contrast to, for example, the penicillin binding proteins (PBPs) from several bacterial species.…”

“…Drug selectivity has both thermodynamic and kinetic components enabling compound selection and optimization to be guided by both the affinity for the target as well as the rate constants for formation and breakdown of the drug-target complex. ,,− In our efforts to delineate the factors that underly the implementation of kinetic selectivity, we identified target vulnerability and target turnover as critical factors in modulating the translation of extended target occupancy to prolonged drug activity. , In antibacterial space, time-dependent drug activity can be assessed using the postantibiotic effect (PAE), which is the delay in bacterial growth following compound washout . While several mechanisms can be responsible for the PAE, we previously described correlations between drug-target residence time and PAE demonstrating that the ribosome and the LpxC enzyme from P.…”

“…In addition to traditional challenges faced by antibacterial drug discovery, , such as drug penetration/efflux, the rapid emergence of resistance, and the lack of target conservation across pathogens, the growth conditions used for establishing the importance of a target for bacterial growth may differ from the environment experienced by the bacteria during human infection. In addition, we and others have posited that target vulnerability plays a major role in the context of target druggability and may have a direct impact on the drug levels required for in vivo antibacterial activity. − …”

“…Target vulnerability quantifies the level of target occupancy required to induce the desired physiological response, such as bacterial cell death. − High vulnerability targets are those that require low levels of occupancy to trigger the desired outcome while low vulnerability targets require high levels of occupancy. Target vulnerability is thus an important factor in determining the drug exposure required for the pharmacodynamic response.…”

“…Recently, we demonstrated that the postantibiotic effect (PAE), which is the delay in bacterial growth following compound washout, could provide insight into target vulnerability and specifically whether an increase in the residence time of the compound on the target translates to an increase in PAE. , Using this approach, we demonstrated that the bacterial ribosome and Pseudomonas aeruginosa LpxC (paLpxC) both exhibit a strong correlation between residence time and PAE, indicating that both are highly vulnerable. , In the present work, we extend the analysis to the LpxC enzyme from Escherichia coli (ecLpxC). LpxC (UDP-3- O -acyl- N -acetylglucosamine deacetylase) catalyzes the first committed step in lipopolysaccharide biosynthesis and is a validated antibacterial target in Gram-negative pathogens. , In contrast to paLpxC, inhibitors of ecLpxC show no PAE in Escherichia coli.…”