Scalable and Chromatography-Free Synthesis of Efflux Pump Inhibitor Phenylalanine Arginine β-Naphthylamide for Its Validation in Wild-Type Bacterial Strains.

Autor: Russo CM; Department of Chemistry, Villanova University, Villanova, PA 19085, USA., Howey KG; Department of Chemistry, Villanova University, Villanova, PA 19085, USA., O'Reilly MC; Department of Chemistry, Villanova University, Villanova, PA 19085, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2023 Jul 17; Vol. 18 (14), pp. e202300128. Date of Electronic Publication: 2023 May 10.
DOI: 10.1002/cmdc.202300128
Abstrakt: Phenylalanine arginine β-naphthylamine, or PAβN, is a C-terminus capped dipeptide discovered in 1999 as an RND-type efflux pump inhibitor (EPI). Since then, PAβN has become a standard tool compound in EPI research and development. Despite this, PAβN lacks a detailed or efficient synthesis, and standard parameters for its use in wild-type bacterial strains are inconsistent or non-existent. Therefore, a scalable and chromatography-free synthesis of PAβN was developed using streamlined traditional solution-phase peptide coupling chemistry. With this procedure, gram scale quantities of PAβN were synthesized alongside analogues and stereoisomers to build a focused library to evaluate simple structure activity relationships. While most analogues were less active than the broadly utilized L,L-PAβN itself, we identified that its enantiomer, D,D-PAβN, also provided 8- to 16-fold potentiation of the antibiotic levofloxacin at 40 to 50 μg/mL concentrations of EPI in various wild-type Pseudomonas aeruginosa strains. Additionally, D,D-PAβN was shown to be significantly more hydrolytically stable than L,L-PAβN, indicating that it may be a useful, and now readily synthesized, tool compound facilitating future EPI research.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
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