Synthesis and Antimicrobial Activity of Burkholderia-Related 4-Hydroxy-3-methyl-2-alkenylquinolines (HMAQs) and Their N-Oxide Counterparts

Abstract

The Burkholderia genus offers a promising potential in medicine because of the diversity of biologically active natural products encoded in its genome. Some pathogenic Burkholderia spp. biosynthesize a specific class of antimicrobial 2-alkyl-4(1H)-quinolones, i.e., 4hydroxy-3-methyl-2-alkenylquinolines (HMAQs) and their N-oxide derivatives (HMAQNOs). Herein, we report the synthesis of a series of six HMAQs and HMAQNOs featuring a trans-Δ 2 double bond at the C2-alkyl chain. The quinolone scaffold was obtained via the Conrad− Limpach approach, while the (E)-2-alkenyl chain was inserted through Suzuki−Miyaura cross-coupling under microwave radiation without noticeable isomerization according to the optimized conditions. Subsequent oxidation of enolate-protected HMAQs cleanly led to the formation of HMAQNOs following cleavage of the ethyl carbonate group. Synthetic HMAQs and HMAQNOs were evaluated in vitro for their antimicrobial activity against different Gramnegative and Gram-positive bacteria as well as against molds and yeasts. The biological results support and extend the potential of HMAQs and HMAQNOs as antimicrobials, especially against Gram-positive bacteria. We also confirm the involvement of HMAQs in the autoregulation of the Hmq system in Burkholderia ambifaria.

Burkholderia thailandensis Methylated Hydroxyalkylquinolines: Biosynthesis and Antimicrobial Activity in Cocultures

“…We hypothesized that BTH_II1576 is a HMAQ with a C 9 carbon chain (HMAQ-C 9:2= ) was purified as described in reference 21. HMAQ-NO congeners were synthesized as described in Materials and Methods and Piochon et al (31). HAQ-NO with a C 7 carbon chain (HQNO) and HAQ with a C 7 carbon chain (HHQ) were purchased from commercial sources (Cayman Chemicals and Sigma Aldrich, respectively).…”

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

“…Our results suggest that the Hmq system of Bcc is non-essential for pathogenicity but could be required for adaption to a particular environmental niche by, for example, influencing rhizosphere microbial community (Vial et al, 2008;Kilani-Feki et al, 2011Mahenthiralingam et al, 2011;Patten et al, 2012;Chapalain et al, 2013Chapalain et al, , 2017Gomes et al, 2018;Le Guillouzer, 2018;Jung et al, 2018;Mullins et al, 2019;Whalen et al, 2019;Piochon et al, 2020). It will be interesting to investigate a possible correlation between the presence of the hmqABCDEFG in Bcc species and their evolutionary trajectory.…”

“…Several studies report novel molecules belonging to the HAQ family and various bacterial species having antimicrobial activities (Wratten et al, 1977;Hamasaki et al, 2000;Whalen et al, 2014;Meyer et al, 2017;Dow et al, 2019). Only a few functions of HMAQs are known, apart from intra and interspecies QS signal (Vial et al, 2008;Chapalain et al, 2017;Le Guillouzer, 2018), especially as antimicrobialshaving a lower activity than antibiotics -however, their main function remains enigmatic (Mori et al, 2007;Kilani-Feki et al, 2011Mahenthiralingam et al, 2011;Li et al, 2018;Piochon et al, 2020). Nonetheless, given the demonstrated role of HAQs and PQS in P. aeruginosa, HMAQs may also play a role in the virulence and pathogenicity of opportunistic Burkholderia pathogens (Vial et al, 2008(Vial et al, , 2009Chapalain et al, 2017).…”

Bacterial Alkyl-4-quinolones: Discovery, Structural Diversity and Biological Properties

“…The methyl-alkylquinolone-N-oxides (MAQNOs) were found to be more active and exhibited strong activity against gram-positive bacteria (B. subtilis, S. aureus, Streptococcus agalactiae, and Paenibacillus peori), but displayed only weak activity against gram-negative bacteria (Actinobacillus pleuropneumoniae, Xanthomonas campestris). For the HMAQs, an increase in chain length were found to increase the activity against A. pleuropneumoniae, B. subtilis, and S. aureus, but the activity was much weaker in comparison to that of MAQNOs [65].…”

“…C9∆2 from outer membrane vesicles (OMVs) of B. thailandensis displayed anti-fungal activity at 100 µM against C. albicans and Cryptococcus neoformans [63]. Microbial alkylquinolones C7∆2, C8∆2, C9∆2, obtained by employing Conrad−Limpach approach and Suzuki−Miyaura coupling reactions, showed moderate activity against C. neoformans [65]. Overall, for anti-fungal and anti-oocyte activity of the alkylquinolones, methylation of position-3 and the presence of an unsaturated alkyl chain at C-2 are strong predictors of antifungal activity.…”