RESUMO
OBJECTIVES: The primary objective of this report is to describe the implementation of a pilot pharmacist-run transitions of care clinic. The secondary objective is to present data collected on the impact of this clinic in regard to 30-day, all-cause hospital readmission rates and provider acceptance rates of pharmacist recommendations. SETTING: This transitions of care clinic was implemented in a Department of Veterans Affairs ambulatory care center located in Columbus, Ohio. PRACTICE DESCRIPTION: Pharmacists saw high-acuity patients who met inclusion criteria in the transitions of care clinic to complete medication reconciliation, disease state education, and medication counseling. After the visit, the pharmacist made recommendations to the patient's primary care provider. PRACTICE INNOVATION: This transitions of care clinic is unique in that it is solely pharmacist-run and is located within a primary care setting. EVALUATION: The impact of the pharmacist-run clinic was evaluated against a matched control group via a retrospective chart review. A chi-square test was run to assess the difference in 30-day, all-cause hospital readmission rates between patients seen in the transitions of care clinic and those who were not. RESULTS: There was a statistically insignificant difference in 30-day, all-cause hospital readmission rates between the transitions of care and control groups (13% vs. 26.1%; P = 0.265). For secondary outcomes assessed in the transitions of care group, 32.9% of medication-related recommendations, 47.4% of laboratory blood work recommendations, and 48.6% of care coordination referrals made by pharmacists were accepted by providers. CONCLUSION: Pharmacist involvement in the transitions of care process in the primary care setting through the implementation of a pharmacist-run clinic may decrease the likelihood of hospital readmission.
Assuntos
Farmacêuticos , Serviço de Farmácia Hospitalar , Humanos , Reconciliação de Medicamentos , Ohio , Alta do Paciente , Readmissão do Paciente , Transferência de Pacientes , Papel Profissional , Estudos RetrospectivosRESUMO
One third of all drugs in clinical use owe their pharmacological activity to the functional inhibition of enzymes, highlighting the importance of enzymatic targets for drug development. Because of the close relationship between inhibition and catalysis, understanding the recognition and turnover of enzymatic substrates is essential for rational drug design. Although the Staphylococcus aureus enoyl-acyl carrier protein reductase (saFabI) involved in bacterial fatty acid biosynthesis constitutes a very promising target for the development of novel, urgently needed anti-staphylococcal agents, the substrate binding mode and catalytic mechanism remained unclear for this enzyme. Using a combined crystallographic, kinetic, and computational approach, we have explored the chemical properties of the saFabI binding cavity, obtaining a consistent mechanistic model for substrate binding and turnover. We identified a water-molecule network linking the active site with a water basin inside the homo-tetrameric protein, which seems to be crucial for the closure of the flexible substrate binding loop as well as for an effective hydride and proton transfer during catalysis. On the basis of our results, we also derive a new model for the FabI-ACP complex that reveals how the ACP-bound acyl-substrate is injected into the FabI binding crevice. These findings support the future development of novel FabI inhibitors that target the FabI-ACP interface leading to the disruption of the interaction between these two proteins.
Assuntos
Proteínas de Bactérias/química , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Modelos Moleculares , Staphylococcus aureus/enzimologia , Água/química , Catálise , Domínio Catalítico , Relação Estrutura-AtividadeRESUMO
Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for a series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI)--an important target for the development of new anti-staphylococcal drugs--as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient, and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Because of its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 h. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme.
Assuntos
Enoil-(Proteína de Transporte de Acila) Redutase (NADPH, B-Específica)/química , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Inibidores Enzimáticos/farmacologia , Proteínas de Escherichia coli/química , Ácido Graxo Sintase Tipo II/química , Staphylococcus aureus/enzimologia , Catálise , Química Farmacêutica , Cristalografia por Raios X , Desenho de Fármacos , Escherichia coli/metabolismo , Ácidos Graxos/química , Ligação de Hidrogênio , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Termodinâmica , Fatores de TempoRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a serious health threat worldwide, and novel antibiotics are therefore urgently needed. The enoyl-ACP reductase (saFabI) is essential for the S. aureus fatty acid biosynthesis and, hence, serves as an attractive drug target. We have obtained a series of snapshots of this enzyme that provide a mechanistic picture of ligand and inhibitor binding, including a dimer-tetramer transition combined with extensive conformational changes. Significantly, our results reveal key differences in ligand binding and recognition compared to orthologous proteins. The remarkable observed protein flexibility rationalizes our finding that saFabI is capable of efficiently reducing branched-chain fatty acid precursors. Importantly, branched-chain fatty acids represent a major fraction of the S. aureus cell membrane and are crucial for its in vivo fitness. Our discovery thus addresses a long-standing controversy regarding the essentiality of the fatty acid biosynthesis pathway in S. aureus rationalizing saFabI as a drug target.