Inhibitor design to target a unique feature in the folate pocket of Staphylococcus aureus dihydrofolate reductase

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Staphylococcus aureus (Sa) is a serious concern due to increasing resistance to antibiotics. The bacterial dihydrofolate reductase enzyme is effectively inhibited by trimethoprim, a compound with antibacterial activity. Previously, we reported a trimethoprim derivative containing an acryloyl linker and a dihydophthalazine moiety demonstrating increased potency against S. aureus. We have expanded this series and assessed in vitro enzyme inhibition (Ki) and whole cell growth inhibition properties (MIC). Modifications were focused at a chiral carbon within the phthalazine heterocycle, as well as simultaneous modification at positions on the dihydrophthalazine. MIC values increased from 0.0626-0.5 μg/mL into the 0.5-1 μg/mL range when the edge positions were modified with either methyl or methoxy groups. Changes at the chiral carbon affected Ki measurements but with little impact on MIC values. Our structural data revealed accommodation of predominantly the S-enantiomer of the inhibitors within the folate-binding pocket. Longer modifications at the chiral carbon, such as p-methylbenzyl, protrude from the pocket into solvent and result in poorer Ki values, as do modifications with greater torsional freedom, such as 1-ethylpropyl. The most efficacious Ki was 0.7 ± 0.3 nM, obtained with a cyclopropyl derivative containing dimethoxy modifications at the dihydrophthalazine edge. The co-crystal structure revealed an alternative placement of the phthalazine moiety into a shallow surface at the edge of the site that can accommodate either enantiomer of the inhibitor. The current design, therefore, highlights how to engineer specific placement of the inhibitor within this alternative pocket, which in turn maximizes the enzyme inhibitory properties of racemic mixtures.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:200

Enthalten in:

European journal of medicinal chemistry - 200(2020) vom: 15. Aug., Seite 112412

Sprache:

Englisch

Beteiligte Personen:

Muddala, N Prasad [VerfasserIn]
White, John C [VerfasserIn]
Nammalwar, Baskar [VerfasserIn]
Pratt, Ian [VerfasserIn]
Thomas, Leonard M [VerfasserIn]
Bunce, Richard A [VerfasserIn]
Berlin, K Darrell [VerfasserIn]
Bourne, Christina R [VerfasserIn]

Links:

Volltext

Themen:

2,4-Diaminopyrimidine
AN164J8Y0X
Alkyl dihydrophthalazines
Antibacterial
Dihydrofolate reductase
EC 1.5.1.3
Enzyme Inhibitors
Enzyme inhibition
Folate pathway
Heck coupling
Journal Article
Staphylococcal aureus
Tetrahydrofolate Dehydrogenase
Trimethoprim

Anmerkungen:

Date Completed 23.10.2020

Date Revised 16.08.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.ejmech.2020.112412

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM310824109