期刊
ACS CHEMICAL BIOLOGY
卷 8, 期 10, 页码 2192-2200出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb400345h
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资金
- Robert A. Welch Foundation [F-1572]
- Loyola University Chicago
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]
The Pseudomonas aeruginosa enzyme PvdQ can process different substrates involved in quorum-sensing or in siderophore biosynthesis. Substrate selectivity was evaluated using steady-state kinetic constants for hydrolysis of N-acyl-homoserine lactones (HSLs) and p-nitrophenyl fatty acid esters. PvdQ prefers substrates with alkyl chains between 12 and 14 carbons long that do not bear a 3-oxo substitution and is revealed here to have a relatively high specificity constant for selected N-acyl-HSLs (k(cat)/K-M = 10(5) to 10(6) M-1 s(-1)). However, endogenous P. aeruginosa N-acyl-HSLs are >= 100-fold disfavored, supporting the conclusion that PvdQ was not primarily evolved to regulate endogenous quorum-sensing. PvdQ plays an essential biosynthetic role for the siderophore pyoverdine, on which P. aeruginosa depends for growth in iron-limited environments. A series of alkylboronate inhibitors was found to be reversible, competitive, and extremely potent (K-i >= 190 pM). A 1.8 angstrom X-ray structure shows that 1-tridecylboronic acid forms a monocovalent bond with the N-terminal beta-chain Ser residue in the PvdQ heterodimer, mimicking a reaction transition state. This boronic acid inhibits growth of P. aeruginosa in iron-limited media, reproducing the phenotype of a genetic pvdQ disruption, although co-administration of an efflux pump inhibitor is required to maintain growth inhibition. These findings support the strategy of designing boron-based inhibitors of siderophore biosynthetic enzymes to control P. aeruginosa infections.
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