Natural Product Inhibition and Enzyme Kinetics Related to Phylogenetic Characterization for Bacterial Peptidyl-tRNA Hydrolase 1

Autor: Hana McFeeters, Robert L. McFeeters, D Scott Strange, Steven S Gaffin, W. Blake Holloway, Jacob N Wisotsky, Meredyth D Kinsella
Jazyk: angličtina
Rok vydání: 2021
Předmět:
medicine.drug_class
Structural similarity
novel antibiotic target
protein biosynthesis
Antibiotics
Pharmaceutical Science
Biology
medicine.disease_cause
Article
Analytical Chemistry
Substrate Specificity
lcsh:QD241-441
03 medical and health sciences
chemistry.chemical_compound
lcsh:Organic chemistry
Drug Discovery
Hydrolase
broad- and narrow-spectrum inhibition
medicine
Enzyme kinetics
Physical and Theoretical Chemistry
peptidyl-tRNA hydrolase
Phylogeny
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Biological Products
Natural product
Phylogenetic tree
Bacteria
phylogenetic analysis
030302 biochemistry & molecular biology
Organic Chemistry
Pathogenic bacteria
natural product inhibition
Anti-Bacterial Agents
Kinetics
Enzyme
chemistry
Biochemistry
Solubility
Chemistry (miscellaneous)
Molecular Medicine
Carboxylic Ester Hydrolases
Zdroj: Molecules
Volume 26
Issue 8
Molecules, Vol 26, Iss 2281, p 2281 (2021)
ISSN: 1420-3049
DOI: 10.3390/molecules26082281
Popis: With the relentless development of drug resistance and re-emergence of many pathogenic bacteria, the need for new antibiotics and new antibiotic targets is urgent and growing. Bacterial peptidyl-tRNA hydrolase, Pth1, is emerging as a promising new target for antibiotic development. From the conserved core and high degree of structural similarity, broad-spectrum inhibition is postulated. However, Pth1 small-molecule inhibition is still in the earliest stages. Focusing on pathogenic bacteria, herein we report the phylogenetic classification of Pth1 and natural product inhibition spanning phylogenetic space. While broad-spectrum inhibition is found, narrow-spectrum and even potentially clade-specific inhibition is more frequently observed. Additionally reported are enzyme kinetics and general in vitro Pth1 solubility that follow phylogenetic boundaries along with identification of key residues in the gate loop region that appear to govern both. The studies presented here demonstrate the sizeable potential for small-molecule inhibition of Pth1, improve understanding of Pth enzymes, and advance Pth1 as a much-needed novel antibiotic target.
Databáze: OpenAIRE
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