Bromination of alkyl quinolones by Microbulbifer sp. HZ11, a marine Gammaproteobacterium, modulates their antibacterial activity

Abstract

Summary Alkyl quinolones (AQs) are multifunctional bacterial secondary metabolites generally known for their antibacterial and algicidal properties. Certain representatives are also employed as signalling molecules of Burkholderia strains and Pseudomonas aeruginosa. The marine Gammaproteobacterium Microbulbifer sp. HZ11 harbours an AQ biosynthetic gene cluster with unusual topology but does not produce any AQ‐type metabolites under laboratory conditions. In this study, we demonstrate the potential of strain HZ11 for AQ production by analysing intermediates and key enzymes of the pathway. Moreover, we demonstrate that exogenously added AQs such as 2‐heptyl‐1(H)‐quinolin‐4‐one (referred to as HHQ) or 2‐heptyl‐1‐hydroxyquinolin‐4‐one (referred to as HQNO) are brominated by a vanadium‐dependent haloperoxidase (V‐HPOHZ11), which preferably is active towards AQs with C5–C9 alkyl side chains. Bromination was specific for the third position and led to 3‐bromo‐2‐heptyl‐1(H)‐quinolin‐4‐one (BrHHQ) and 3‐bromo‐2‐heptyl‐1‐hydroxyquinolin‐4‐one (BrHQNO), both of which were less toxic for strain HZ11 than the respective parental compounds. In contrast, BrHQNO showed increased antibiotic activity against Staphylococcus aureus and marine isolates. Therefore, bromination of AQs by V‐HPOHZ11 can have divergent consequences, eliciting a detoxifying effect for strain HZ11 while simultaneously enhancing antibiotic activity against other bacteria.

Modification of the Pseudomonas aeruginosa toxin 2‐heptyl‐1‐hydroxyquinolin‐4(1H)‐one and other secondary metabolites by methyltransferases from mycobacteria

“…3‐Bromo‐2‐heptyl‐1‐hydroxyquinolin‐4(1 H )‐one [62] ( 10 ) (35 mg, 0.10 mmol) was dissolved in methanol (4 mL) and dichloromethane (2 mL). Trimethylsilyldiazomethane (2 m solution in diethyl ether; 0.2 mL, 0.4 mmol, 4.0 equiv.)…”

“…The following compounds were synthesized according to literature: 1‐hydroxyquinolin‐4(1 H )‐one ( 2 ) [60], 3‐bromo‐2‐heptylquinolin‐4(1 H )‐one ( 5 ) [61], HMOQ ( 11 ) [25], 3‐bromo‐2‐heptyl‐1‐hydroxyquinolin‐4(1 H )‐one ( 10 ) [62], HHQ ( 4 ), 2‐heptyl‐1‐methylquinolin‐4(1 H )‐one ( 7 ), 2‐heptyl‐3‐hydroxy‐1‐methylquinolin‐4(1 H )‐one ( 8 ), HQNO ( 9 ), 2‐heptyl‐4‐methoxyquinoline‐1‐oxide ( 14 ), 2‐heptyl‐4‐methoxyquinoline ( 15 ) and 2‐heptyl‐3‐hydroxy‐4‐methoxyquinoline ( 16 ) [58]. 4‐Methoxyisoquinolin‐1(2 H )‐one ( 22 ) was bought from AnalytiCon Discovery (Potsdam, Germany).…”

“…Volatiles were removed under vacuum, and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH: 20/1) to provide the product 3 (8 mg, 0.046 mmol, 49%) as a colorless oil. 1 Synthesis of 3-bromo-2-heptyl-1methoxyquinolin-4(1H)-one (12) 3-Bromo-2-heptyl-1-hydroxyquinolin-4(1H)-one [62] (10) (35 mg, 0.10 mmol) was dissolved in methanol (4 mL) and dichloromethane (2 mL). Trimethylsilyldiazomethane (2 M solution in diethyl ether; 0.2 mL, 0.4 mmol, 4.0 equiv.)…”

Presence of the Hmq system and production of 4-hydroxy-3-methyl-2-alkylquinolines is heterogeneously distributed betweenBurkholderia cepaciacomplex species and more prevalent among environmental than clinical isolates

“…The bacterium Pseudomonas aeruginosa carries a distinct QS system whose ligands are not AHLs but instead 4-hydroxy-2-alkylquinolines (HAQs), such as the Pseudomonas Quinolone Signal (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) (Pesci et al, 1999;Déziel et al, 2004;Heeb et al, 2011). Interestingly, some strains of Bcc (B. ambifaria and B. cepacia), as well as B. pseudomallei and B. thailandensis, produce homologous molecules, that we call 4-hydroxy-3methyl-2-alkylquinolines (Diggle et al, 2006;Vial et al, 2008;Ritzmann et al, 2019), that are synthesized by enzymes encoded by the hmqABCDEFG operon (Vial et al, 2008). In contrast with P. aeruginosa HAQs, the main HMAQs produced by Burkholderia bear a methyl group at the 3' position and an unsaturation of the alkyl side chain.…”

An α/β-Hydrolase Fold Subfamily Comprising Pseudomonas Quinolone Signal-Cleaving Dioxygenases

“…The marine Gammaproteobacterium Microbulbifer sp. strain HZ11, as well as the Gram-positive opportunistic pathogen Staphylococcus aureus, were found to be capable of HHQ hydroxylation at C-3 (22,23). An analogous hydroxylation represents the first step of HHQ degradation by Rhodococcus erythropolis BG34 and Mycobacteroides abscessus subsp.…”