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1.
J Antimicrob Chemother ; 72(3): 744-753, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27999062

RESUMO

Objectives: Biofilm infections of intravascular catheters caused by Staphylococcus aureus may be treated with catheter lock solutions (CLSs). Here we investigated the antibacterial activity, cytotoxicity and CLS potential of 5-hydroxyethyl-3-tetradecanoyltetramic acid (5HE-C14-TMA) compared with the related compounds 3-tetradecanoyltetronic (C14-TOA) and 3-tetradecanoylthiotetronic (C14-TTA), which are variants of quorum sensing signalling molecules produced by Pseudomonas aeruginosa . Methods: Antibacterial activity and mechanism of action of 5HE-C14-TMA, C14-TOA and C14-TTA were determined via MIC, bacterial killing, membrane potential and permeability assays. Susceptibility of S. aureus biofilms formed in the presence of plasma in vitro was investigated, MTT cytotoxicity testing was undertaken and cytokine release in human blood upon exposure to 5HE-C14-TMA and/or S. aureus biofilms was quantified. The effectiveness of 5HE-C14-TMA as CLS therapy in vivo was assessed using a rat intravascular catheter biofilm infection model. Results: MICs of 5HE-C14-TMA, C14-TOA and C14-TTA ranged from 2 to 4 mg/L. 5HE-C14-TMA and C14-TTA were bactericidal; all three compounds perturbed the staphylococcal membrane by increasing membrane permeability, depolarized the transmembrane potential and caused ATP leakage. Cytotoxicity and haemolytic activity were compound and target cell type-dependent. 5HE-C14-TMA reduced S. aureus biofilm viability in a dose-dependent manner in vitro and in vivo and did not trigger release of cytokines in human blood, but inhibited the high levels of IL-8 and TNF-α induced by S. aureus biofilms. Conclusions: 5HE-C14-TMA, C14-TOA and C14-TTA are membrane-active agents. 5HE-C14-TMA was the most potent, eradicating S. aureus biofilms at 512-1024 mg/L both in vitro and in vivo as a CLS.


Assuntos
Antibacterianos/uso terapêutico , Infecções Relacionadas a Cateter/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Dispositivos de Acesso Vascular/microbiologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Infecções Relacionadas a Cateter/microbiologia , Descoberta de Drogas , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Pseudomonas aeruginosa/metabolismo , Pirrolidinonas/farmacologia , Percepção de Quorum , Ratos , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Vancomicina/farmacologia
2.
Environ Microbiol ; 17(11): 4352-65, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25809238

RESUMO

In Pseudomonas aeruginosa, quorum sensing (QS) regulates the production of secondary metabolites, many of which are antimicrobials that impact on polymicrobial community composition. Consequently, quenching QS modulates the environmental impact of P. aeruginosa. To identify bacteria capable of inactivating the QS signal molecule 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a minimal medium containing PQS as the sole carbon source was used to enrich a Malaysian rainforest soil sample. This yielded an Achromobacter xylosoxidans strain (Q19) that inactivated PQS, yielding a new fluorescent compound (I-PQS) confirmed as PQS-derived using deuterated PQS. The I-PQS structure was elucidated using mass spectrometry and nuclear magnetic resonance spectroscopy as 2-heptyl-2-hydroxy-1,2-dihydroquinoline-3,4-dione (HHQD). Achromobacter xylosoxidans Q19 oxidized PQS congeners with alkyl chains ranging from C1 to C5 and also N-methyl PQS, yielding the corresponding 2-hydroxy-1,2-dihydroquinoline-3,4-diones, but was unable to inactivate the PQS precursor HHQ. This indicates that the hydroxyl group at position 3 in PQS is essential and that A. xylosoxidans inactivates PQS via a pathway involving the incorporation of oxygen at C2 of the heterocyclic ring. The conversion of PQS to HHQD also occurred on incubation with 12/17 A. xylosoxidans strains recovered from cystic fibrosis patients, with P. aeruginosa and with Arthrobacter, suggesting that formation of hydroxylated PQS may be a common mechanism of inactivation.


Assuntos
Achromobacter denitrificans/metabolismo , Pseudomonas aeruginosa/metabolismo , Quinolonas/metabolismo , Percepção de Quorum/fisiologia , Metabolismo Secundário/fisiologia , Dados de Sequência Molecular , Oxirredução , Floresta Úmida , Transdução de Sinais , Solo/química , Microbiologia do Solo
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