Potential of the Burkholderia cepacia Complex to Produce 4-Hydroxy-3-Methyl-2-Alkyquinolines

Coulon, Pauline M. L.; Groleau, Marie‐Christine; Déziel, Éric

doi:10.3389/fcimb.2019.00033

Cited by 28 publications

(46 citation statements)

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“…A few of them have analogous biosynthesis pathways in other Burkholderia species or even beyond the Burkholderia. For example, the hmqABCDEFG operon coding for enzymes responsible for the biosynthesis of a family of antimicrobial quinolones named 4-hydroxy-3-methyl-2-alkenylquinolines (HMAQs) are found in B. pseudomallei and other members of the Burkholderia genus such as Burkholderia ambifaria (21). The products of the hmq genes have varying carbon chain lengths and the relative abundance of these molecules differs between species.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

Klaus

Majerczyk

Eppler

et al. 2020

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“…Pseudomonas aeruginosa and some Burkholderia species [23,24]. Quinolones of this class are classified into two lineages, those with or without a 3-methyl group, and the latter lineages are unique to Burkholderia producers [25].…”

Section: Connection Of This Unit To C4a Of the Benzene Ring Was Implimentioning

confidence: 99%

“…Quinolones of this class are classified into two lineages, those with or without a 3-methyl group, and the latter lineages are unique to Burkholderia producers [25]. These metabolites are shown to be biosynthesized by head-to-head condensation of anthranilate and ketoacylate precursors, followed by modification at C3 or nitrogen by putative monooxygenases or methyltransferase [24]. Entry of malonate as the acylate precursor into this pathway is proposed to yield 4HQ [26].…”

Section: Connection Of This Unit To C4a Of the Benzene Ring Was Implimentioning

confidence: 99%

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

Li¹,

Oku²,

Shinozaki³

et al. 2020

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4-Hydroxy-3-methyl-2(1H)-quinolone (1), an old synthetic molecule and recently discovered from a plant without providing sufficient evidence to support the structure, was isolated from a fermentation extract of Burkholderia sp. 3Y-MMP isolated from a soil by a Zn2+ enrichment culture. Detailed spectroscopic analyses by MS and NMR, combined with 13C chemical shift comparison with literature values of the related compounds and a synthetic preparation of 1, allowed its first full NMR characterization and identification of 4-hydroxy-2-quinolone but not 4-hydroxy-2-quinolinol as the preferred tautomer for this heterocyclic system. While the metal-chelating activity was negligible, 1 at 100 mM quenched hydroxy radical-induced chemiluminescence emitted by luminol by 86%. Because some Burkholderia species are pathogenic to plants and animals, the above result suggests that 1 is a potential antioxidant to counteract reactive oxygen species-based immune response in the host organisms.

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“…B. territorii, and B. ubonensis species carry the hmqABCDEFG operon, but not all strains within a species, while B. anthina, B. arboris B. cenocepacia, B. diffusa, B. latens, B. metallica, B. multivorans, B. pseudomultivorans, B. seminalis, B.stabilis and B. vietnamiensis -species mainly found in clinical cases -are lacking hmqABCDEFG operon (Coulon et al, 2019). To experimentally validate our in silico study and verify the ability of Bcc isolates carrying the hmqABCDEFG operon to actually produce HMAQs, a collection of 313 Bcc strains, comprising 222 clinical and 91 environmental isolates belonging to 18 different Bcc species, was analyzed to first determine the presence of the hmqABCDEFG operon in their genome.…”

Section: Introductionmentioning

confidence: 99%

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

Coulon

Zlosnik

Déziel

2020

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Some Burkholderia cepacia complex (Bcc) strains have been reported to produce 4-hydroxy-3-methyl-2-alkylquinolines (HMAQs), analogous to the 4-hydroxy-2-alkylquinolines of Pseudomonas aeruginosa. Using in silico analyses, we previously showed that the hmqABCDEFG operon, which encodes enzymes involved in the biosynthesis of HMAQs, is carried by about one-third of Bcc strains, with considerable inter- and intra-species variability. In the present study, we investigated by PCR, using consensus primers, the distribution of hmqABCDEFG in a collection of 313 Bcc strains (222 of clinical and 91 of environmental origins) - belonging to 18 Bcc species. We confirmed that the distribution is species-specific, although not all strains within a species carry the hmqABCDEFG operon. Among the 30% of strains bearing the hmqABCDEFG operon, we measured the total HMAQs production and showed that 90% of environmental isolates and 68% of clinically isolated Bcc produce detectable levels of HMAQs when cultured in TSB medium. For the strains having the hmqABCDEFG operon but not producing HMAQs, we studied the transcription and showed that none expressed the hmqA gene under the specified culture conditions. Interestingly, the hmqABCDEFG operon is more prevalent among plant root environment species (e.g. B. ambifaria, B. cepacia) and absent in species commonly found in chronically colonized individuals with cystic fibrosis (e.g. B. cenocepacia, B. multivorans), suggesting that the Hmq system could play a role in niche adaptation by influencing rhizosphere microbial community and could have been lost through evolution. Understanding the Hmq system and its regulation will provide clues concerning the production of HMAQs and their functions in Bcc.

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Potential of the Burkholderia cepacia Complex to Produce 4-Hydroxy-3-Methyl-2-Alkyquinolines

Cited by 28 publications

References 71 publications

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

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

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

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

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