Synthesis of Pseudomonas quorum-sensing autoinducer analogs and structural entities required for induction of apoptosis in macrophages

Pseudomonas aeruginosa, an opportunistic pathogen, is known to mainly use N-acylhomoserine lactones (AHLs) as autoinducers. Recent progress in this field demonstrated that not only AHLs, but also their degradation products, tetramic acids, may have some biological activities. The present study examined the roles of Pseudomonas autoinducers and tetramic acids in bacterial survival and behavior in ecological niches. P. aeruginosa autoinducers and the tetramic acid derivatives were chemically synthesized, and the structure-activity correlation was investigated. Some tetramic acids derived from AHLs caused a significant reduction in the viability of P. aeruginosa in a concentration dependent manner (30-300 μM). The smaller the inoculum of bacteria, the stronger the bactericidal activity that was observed. The data from tetramic acid derivatives indicated the keto-enol structure of tetramic acid to be critical for the antibacterial activity. Exogenous tetramic acid did not induce significant changes in the formation of biofilm or production of exoproducts such as pyocyanin and elastase. Tetramic acid and disinfectants acted synergistically to kill P. aeruginosa. These results suggest the AHL-degradation product tetramic acid to be useful for bacterial control.

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“…aeruginosa autoinducers and TA derivatives were chemically synthesized, as described previously (12,15) (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Roles of Pseudomonas aeruginosa Autoinducers and their Degradation Products, Tetramic acids, in Bacterial Survival and Behavior in Ecological Niches

et al. 2011

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“…aeruginosa autoinducers and TAs used. P. aeruginosa autoinducers (3-oxo-C 12 -HSL, C 4 -HSL) and other acyl-HSL analogs as precursors of TAs (TA1 to TA7) were chemically synthesized, as described previously (11,20). Conversion of the acyl-HSL analogs into TAs (TA1 to TA7) was basically done by the procedure previously described for the preparation of TA1 (14) (Fig.…”

Section: Methodsmentioning

confidence: 99%

Anti- Clostridium difficile Potential of Tetramic Acid Derivatives from Pseudomonas aeruginosa Quorum-Sensing Autoinducers

Ueda

Tateda

Horikawa

et al. 2010

Antimicrob Agents Chemother

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We have examined the potential bactericidal activities of several tetramic acids derived from Pseudomonas autoinducers against Clostridium difficile, a cause of antibiotic-associated pseudomembranous colitis. Clinical isolates of C. difficile (n ‫؍‬ 4) were incubated in broth with a chemically synthesized Pseudomonas autoinducer and its tetramic acid derivatives. The structure-activity relationship and the mechanisms of action were examined by a time-killing assay and by determination of the morphological/ staining characteristics. The use of some tetramic acids derived from N-3-oxododecanoyl L-homoserine lactone resulted in more than 3-log reductions in the viability of C. difficile within 30 min at 30 M. The outer membrane was suggested to be one of the targets for the bactericidal activity of tetramic acid, because disturbance of the bacterial outer surface was demonstrated by alteration of the Gram-staining characteristic and electron microscopy. The data for the tetramic acid derivatives demonstrate that the keto-enol structure and the length of the acyl side chain of tetramic acid may be essential for the antibacterial activity of this molecule. These results suggest the potential for tetramic acid derivatives to be novel agents with activity against C. difficile.

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“…We synthesized 3-oxo-C 12 -HSL, C 4 -HSL, and several other HSL analogues using the method of Horikawa et al (2006). The synthesized 3-oxo-C 12 -HSL and C 4 -HSL were structurally and functionally identical to the natural molecules produced by Ps.…”

Section: Methodsmentioning

confidence: 99%

Pseudomonas aeruginosa Las quorum sensing autoinducer suppresses growth and biofilm production in Legionella species

et al. 2009

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Bacteria commonly communicate with each other by a cell-to-cell signalling mechanism known as quorum sensing (QS). Recent studies have shown that the Las QS autoinducer N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C 12 -HSL) of Pseudomonas aeruginosa performs a variety of functions not only in intraspecies communication, but also in interspecies and interkingdom interactions. In this study, we report the effects of Pseudomonas 3-oxo-C 12 -HSL on the growth and suppression of virulence factors in other bacterial species that frequently co-exist with Ps. aeruginosa in nature. It was found that 3-oxo-C 12 -HSL, but not its analogues, suppressed the growth of Legionella pneumophila in a dose-dependent manner. However, 3-oxo-C 12 -HSL did not exhibit a growth-suppressive effect on Serratia marcescens, Proteus mirabilis, Escherichia coli, Alcaligenes faecalis and Stenotrophomonas maltophilia. A concentration of 50 mM 3-oxo-C 12 -HSL completely inhibited the growth of L. pneumophila. Additionally, a significant suppression of biofilm formation was demonstrated in L. pneumophila exposed to 3-oxo-C 12 -HSL. Our results suggest that the Pseudomonas QS autoinducer 3-oxo-C 12 -HSL exerts both bacteriostatic and virulence factor-suppressive activities on L. pneumophila alone. INTRODUCTIONBacteria respond and adapt to a constantly changing environment because they have to compete with other micro-organisms for nutrients. To sense their own environmental conditions, bacteria utilize quorum sensing (QS) systems that operate via small molecules known as autoinducers (Miller & Bassler, 2001). These systems regulate the expression of a number of genes synchronously across the bacterial population. Gram-negative bacteria utilize lipid-based molecules, termed acylhomoserine lactones (AHLs) to communicate with each other, whereas Gram-positive bacteria employ peptide-based molecules, termed autoinducing peptides (Federle & Bassler, 2003;Fuqua & Greenberg, 2002). Autoinducer-2 has been found in a variety of bacteria and is considered to be a universal QS molecule (Xavier & Bassler, 2003). When an autoinducer accumulates to the threshold concentration in a populationdensity manner, the expression triggers induction or repression of certain sets of genes that co-ordinate the behaviour of the bacterial population, including the expression of virulence factors. The mechanisms of QS have been extensively characterized in the pathogenic bacterium Pseudomonas aeruginosa, an important causative agent of nosocomial respiratory and urinary tract infections (Willcox et al., 2008). Ps. aeruginosa produces several virulence factors, including LasB elastase, rhamnolipids, pyocyanin, lipase and hydrogen cyanide that contribute to its pathogenesis (Winstanley & Fothergill, 2009). The las-and rhl-QS systems regulate the production of these virulence factors via N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C 12 -HSL) and N-butanoyl-L-homoserine lactone (C 4 -HSL), respectively. METHODSBacterial strains and culture media. Bacterial strains used ...

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Synthesis of Pseudomonas quorum-sensing autoinducer analogs and structural entities required for induction of apoptosis in macrophages

Cited by 37 publications

References 9 publications

Roles of Pseudomonas aeruginosa Autoinducers and their Degradation Products, Tetramic acids, in Bacterial Survival and Behavior in Ecological Niches

Roles of Pseudomonas aeruginosa Autoinducers and their Degradation Products, Tetramic acids, in Bacterial Survival and Behavior in Ecological Niches

Anti- Clostridium difficile Potential of Tetramic Acid Derivatives from Pseudomonas aeruginosa Quorum-Sensing Autoinducers

Pseudomonas aeruginosa Las quorum sensing autoinducer suppresses growth and biofilm production in Legionella species

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