The Synthesis of Quinolone Natural Products from <i>Pseudonocardia</i> sp.

Salvaggio, Flavia; Hodgkinson, James T.; Carro, L.; Geddis, Stephen M.; Galloway, Warren R. J. D.; Welch, Martin; Spring, David R.

doi:10.1002/ejoc.201501400

Cited by 27 publications

(30 citation statements)

References 38 publications

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“…B. ambifaria strains with pME6010 plasmids were constructed by electroporation as previously described for B. thailandensis (6). Reduction of the quinolone ester followed by halogen substitution led to 2-chloromethyl-3-methylquinolin-4(1H)-ones, which were subjected to Suzuki-Miyaura cross-coupling (34) with commercially available alkenylboronic acid pinacol esters to provide HMAQs.…”

Section: Methodsmentioning

confidence: 99%

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

Klaus

Majerczyk

Eppler

et al. 2020

Preprint

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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: Methodsmentioning

confidence: 99%

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

Klaus

Majerczyk

Eppler

et al. 2020

Preprint

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“…The significant feature is a sp‐sp 3 SMCR between a common boronic ester lateral chain and various functionalized quinolone cores. In attempt to synthesis of these compounds, quinolones bearing different halide substituents 473, 474, 475 and 476 were obtained from readily accessible diester 471 and pinacolborate 477 as well as easily available keton 472 which were subjected to SMCR under microwave irradiation in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium(0) in 1,4‐dioxane to afford the products 467‐470 respectively in good to moderate yields and high purity (Scheme ) …”

Section: Coupling Of Sp3 Hybridised C–b Compoundsmentioning

confidence: 99%

Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

Koshvandi

Heravi

Momeni

2018

Applied Organom Chemis

168

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Suzuki‐Miyaura Coupling Reaction (SMCR) has been extensively used in the total synthesis of natural products. We underscored these achievements in a report published in Tetrahedron up to 2012. Since then, there has been tremendous growth in this field and numerous articles have been published after 2012. In this review, we tried to go insight and highlight the current developments in the applications of SMCR as a key and strategic step (steps) in the total synthesis of biologically active natural products accomplished and reported from 2012 till date.

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“…We wished to investigate the potential of 1 – 8 to modulate QS in P. aeruginosa , however, the compounds are available in only trace amounts from natural sources [ 3 ], and so we embarked on the total synthesis of the compounds. We first developed a strategy which constructed natural products 1 – 4 by uniting the quinolone cores with the side chain by means of an sp 2 –sp 3 Suzuki–Miyaura coupling reaction [ 8 ]. Whilst these compounds unfortunately provided no modulation of PQS quorum screening (as determined using a heterologous Escherichia coli reporter system [ 9 ]), an intriguing effect upon the growth of E. coli and Staphylococcus aureus was noted, which showed an extended lag phase in response to the compounds (except 4 , which was inactive towards E. coli .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

Geddis¹,

Coroama²,

Forrest³

et al. 2018

Beilstein J. Org. Chem.

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A series of analogues of Pseudonocardia sp. natural products were synthesized, which have been reported to possess potent antibacterial activity against Helicobacter pylori and induce growth defects in Escherichia coli and Staphylococcus aureus. Taking inspiration from a methodology used in our total synthesis of natural products, we applied this methodology to access analogues possessing bulky N-substituents, traditionally considered to be challenging scaffolds. Screening of the library provided valuable insights into the structure–activity relationship of the bacterial growth defects, and suggested that selectivity between bacterial species should be attainable. Furthermore, a structurally related series of analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogen Pseudomonas aeruginosa, which may be a result of their similarity to the Pseudomonas quinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in PQS analogues, which has been hitherto underexplored.

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The Synthesis of Quinolone Natural Products from Pseudonocardia sp.

Cited by 27 publications

References 38 publications

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

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

Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

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