Abstract
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.
Highlights
In routine healthcare, use of implantable medical devices, such as intravascular catheters (IVC), has increased significantly
During a search for novel chemical scaffolds for such compounds, we discovered that the Pseudomonas aeruginosa quorum sensing signal molecule, N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) inhibited S. aureus growth at high concentrations (MIC, 100 lM; 30 mg/L).[8,9]
Community-acquired MRSA (CA-MRSA) strain USA300, its isogenic agr mutant,[17] the hospital-acquired MRSA (HA-MRSA) strain BH1CC,[18] the HA-MSSA strain BH4819 and the MSSA strain SH100020 were cultured in Mueller–Hinton broth for susceptibility testing or in RPMI-1640 (Gibco) for biofilm formation
Summary
Use of implantable medical devices, such as intravascular catheters (IVC), has increased significantly. Colonization by surface-adhering bacteria is associated with biofilm formation and subsequent catheter-related bloodstream infection (CRBSI) resulting in significant patient morbidity and mortality, prolonged hospitalization and excess hospital-related costs.[1,2] Staphylococcal biofilms are recognized as the most frequent cause of CRBSI.[3,4] Such biofilms are highly refractory to both the innate immune system and antimicrobial therapy resulting in treatment failure and persistence of infection. While the presence of a Staphylococcus aureus CRBSI usually necessitates systemic antimicrobial therapy along with IVC removal, there are common clinical situations that preclude IVC removal such as the lack of alternative vascular access, patient co-morbidities and bleeding disorders. An alternative treatment approach attempting to salvage the IVC and eradicate the biofilm, involves the combination of systemic antimicrobials and a catheter
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