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

Piochon, Marianne; Coulon, Pauline M. L.; Caulet, Armand; Groleau, Marie‐Christine; Déziel, Éric; Gauthier, Charles

doi:10.26434/chemrxiv.11859144.v1

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“…The antimicrobial properties of alkylquinolones date back to 1945, when an "antibiotic metabolite" was described in P. aeruginosa (41). Although the biosynthesis steps and biology of the alkylquinolones in P. aeruginosa have since been studied in detail, much less is known of those in B. thailandensis (22,32,42). Results of this study add new information to the known steps of biosynthesis of B. thailandensis alkylquinolines.…”

Section: Discussionmentioning

confidence: 84%

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Burkholderia thailandensismethylated hydroxy-alkylquinolines: biosynthesis and antimicrobial activity in co-cultures

Klaus

Majerczyk

Eppler

et al. 2020

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22Lawrence, KS 66045 23 jrchandler@ku.edu 24 25 2 ABSTRACT (179/250 words) 26 The bacterium Burkholderia thailandensis produces an arsenal of secondary metabolites 27 that have diverse structures and roles in the ecology of this soil-dwelling bacterium. In 28 liquid co-culture experiments, B. thailandensis secretes an antimicrobial that nearly 29 eliminates another soil bacterium, Bacillus subtilis. To identify the antimicrobial, we used 30 a transposon mutagenesis approach. This screen identified antimicrobial-defective 31 mutants with insertions in the hmqA, hmqC and hmqF genes involved in biosynthesis of a 32 family of 2-alkyl-4(1H)-quinolones called 4-hydroxy-3-methyl-2-alkenylquinolines 33 (HMAQs), which are closely related to the Pseudomonas aeruginosa 4-hydroxy-2-34 alkylquinolines (HAQs). Insertions also occurred in the previously uncharacterized gene 35 BTH_II1576. Results confirm that BTH_II1576 is involved in generating N-oxide 36 derivatives of HMAQs (HMAQ-NO) in B. thailandensis and that HMAQ-NOs are 37 sufficient to eliminate B. subtilis in co-cultures. Moreover, synthetic HMAQ-NO is ~50-38 fold more active than HMAQ. Both the methyl group and the length of the carbon side 39 chain account for high activity of HMAQ-NO against B. subtilis. The results provide new 40 information on the biosynthesis and activities of HMAQs and reveal new insight into 41 how these molecules might be important for the ecology of B. thailandensis. 42 43 44 45 46 47 48 IMPORTANCE (120 words) 50 The soil bacterium Burkholderia thailandensis produces 2-alkyl-4(1H)-quinolones, 51 mostly methylated 4-hydroxy-alkenylquinolines, a family of relatively unstudied 52 metabolites similar to molecules also synthesized by Pseudomonas aeruginosa. Several 53 of the methylated 4-hydroxy-alkenylquinolines have antimicrobial activity against other 54 species. We show that N-oxidated methyl-alkenylquinolines are particularly antimicrobial 55 and sufficient to kill Bacillus subtilis in co-cultures. We confirmed their biosynthesis 56 requires the previously unstudied protein HmqL. These results provide new information 57 about the biology of 2-alkyl-4(1H)-quinolones, particularly the methylated 4-hydroxy-58 alkenylquinolines, which are unique to B. thailandensis. This study also has importance 59 for understanding B. thailandensis secondary metabolites and has implications for 60 potential therapeutic development. 61 62 64 pathogens, B. pseudomallei and B. mallei, which are the causative agents of melioidosis 65 and glanders, respectively (1, 2). B. pseudomallei is also a saprophyte and causes 66 respiratory or skin infections in humans following exposure to organisms in the 67 environment, such as through skin contact with soil (3). B. mallei is a host-adapted 68 pathogen and is spread to humans from horses and other ungulates, in which it is endemic 69 in some regions (4). Because B. pseudomallei and B. mallei are Tier 1 Select Agents and 70 require handling in BSL-3-level laboratory conditions, B. thailandensis is often used as a ...

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Section: Discussionmentioning

confidence: 84%

“…HMAQ with a C9 carbon chain (HMAQC9:2') was purified as described in (22). HMAQ-NO congeners were synthesized as described in Materials and Methods and Piochon et al (32). HAQ-NO with a C 7 carbon chain (HQNO) and HAQ with a C 7 carbon chain (HHQ) were commercially purchased (Cayman Chemicals and Sigma Aldrich, respectively).…”

Section: Discussionmentioning

confidence: 99%