Abstract
Staphylococcus aureus biofilms are a major problem in modern healthcare due to their resistance to immune system defenses and antibiotic treatments. Certain analgesic agents are able to modulate S. aureus biofilm formation, but currently no evidence exists if paracetamol, often combined with antibiotic treatment, also has this effect. Therefore, we aimed to investigate if paracetamol can modulate S. aureus biofilm formation. Considering that certain regulatory pathways for biofilm formation and virulence factor production by S. aureus are linked, we further investigated the effect of paracetamol on immune modulator production. The in vitro biofilm mass of 21 S. aureus strains from 9 genetic backgrounds was measured in the presence of paracetamol. Based on biofilm mass quantity, we further investigated paracetamol-induced biofilm alterations using a bacterial viability assay combined with N-Acetylglucosamine staining. Isothermal microcalorimetry was used to monitor the effect of paracetamol on bacterial metabolism within biofilms and green fluorescent protein (GFP) promoter fusion technology for transcription of staphylococcal complement inhibitor (SCIN). Clinically relevant concentrations of paracetamol enhanced biofilm formation particularly among strains belonging to clonal complex 8 (CC8), but had minimal effect on S. aureus planktonic growth. The increase of biofilm mass can be attributed to the marked increase of N-Acetylglucosamine containing components of the extracellular matrix, presumably polysaccharide intercellular adhesion. Biofilms of RN6390A (CC8) showed a significant increase in the immune modulator SCIN transcription during co-incubation with low concentrations of paracetamol. Our data indicate that paracetamol can enhance biofilm formation. The clinical relevance needs to be further investigated.
Highlights
Staphylococcus aureus biofilms are a major problem in modern healthcare due to their resistance to immune system defenses and antibiotic treatments
Since paracetamol is frequently being used in the early stages of infection when biofilms are formed[12], we studied the effect of paracetamol exposure on S. aureus biofilm formation using 21 strains from 9 genetic backgrounds, which includes the clinically relevant clonal complex 8 (CC8) strains ST239 and USA300
Since the concentration of paracetamol in human serum is normally below 30 μg/mL25,26, we overnight co-incubated S. aureus with 0.5, 1, 2, 4, 8, 16, and 32 μg/mL of paracetamol. We found that these clinically relevant concentrations of paracetamol had no significant effect on planktonic growth of S. aureus strains, except for some of the strains having a CC8 genetic background (Fig. 1)
Summary
Staphylococcus aureus biofilms are a major problem in modern healthcare due to their resistance to immune system defenses and antibiotic treatments. Considering that certain regulatory pathways for biofilm formation and virulence factor production by S. aureus are linked, we further investigated the effect of paracetamol on immune modulator production. Relevant concentrations of paracetamol enhanced biofilm formation among strains belonging to clonal complex 8 (CC8), but had minimal effect on S. aureus planktonic growth. Acetylsalicylic acid in that it does not induce anti-inflammatory e ffects[20,21] Until now, it has not been investigated if paracetamol has an influence on biofilm formation and development. Considering that the S. aureus regulator pathway for biofilm formation and virulence factor production are correlated[23,24], we studied the impact of paracetamol on the transcription of staphylococcal complement inhibitor (SCIN) protein. SCIN is a potent immune modulator which is able to inhibit host complement activation pathways during the early stages of biofilm formation[12]
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