The Therapeutic Effect of 1,8-Cineol on Pathogenic Bacteria Species Present in Chronic Rhinosinusitis

Abstract

Chronic rhinosinusitis (CRS) is marked by an inflamed mucosa of sinuses and is accompanied by a significantly reduced quality of live. Since no guidelines for the treatment of CRS are available, long lasting clinical histories with health care costs adding up to dozens of billion $ annually are caused by CRS. The progression of CRS is often induced by bacterial infections and/or a shift in microbiome as well as biofilm formation. The exact microbiome alterations are still unclear and the impenetrable biofilm renders the treatment with common antibiotics ineffective. This study focuses on characterizing the microbiome changes in CRS and investigating the inhibition of biofilm growth by 1,8-Cineol, a small, non-polar and hence biofilm penetrating molecule with known antimicrobial potential. We performed MALDI-TOF MS based characterization of the microbiomes of healthy individuals and CRS patients (n = 50). The microbiome in our test group was shifted to pathogens (Staphylococcus aureus, Escherichia coli, and Moraxella catarrhalis). In contrast to published studies, solely based on cell culture techniques, we could not verify the abundance of Pseudomonas aeruginosa in CRS. The inhibition of bacterial proliferation and biofilm growth by 1,8-Cineol was measured for these three pathogens. Interestingly, S. aureus, the most prominent germ in CRS, showed a biofilm inhibition not simply correlated to its inhibition of proliferation. RT-qPCR confirmed that this was due to the downregulations of major key players in biofilm generation (agrA, SarA and σB) by 1,8-Cineol. Furthermore we verified this high biofilm inhibition potential in a model host system consisting out of S. aureus biofilm grown on mature respiratory epithelium. A second host model, comprising organotypic slices, was utilized to investigate the reaction of the innate immune system present in the nasal mucosa upon biofilm formation and treatment with 1,8-Cineol. Interestingly Staphylococcus epidermidis, the cause of very common catheter infections, possesses a biofilm generation pathway very similar to S. aureus and might be treatable in a similar fashion. The two presented in vitro model systems might be transferred to combinations of every biofilm forming bacterial with most kind of epithelium and mucosa.

Preparation of Terpenoid-Invasomes with Selective Activity against S. aureus and Characterization by Cryo Transmission Electron Microscopy

“…In contrast to the strong bactericidal effects against S. aureus, cell Next to Gram-positive bacterial species such as S. aureus, we also investigated potential anti-bacterial properties of our invasomes and particularly, thymol-invasomes on Gram-negative E. coli. Here, cineol-comprising invasomes led to a strong inhibition of E. coli growth, which is in line with our previous observations [13]. In contrast to the strong bactericidal effects against S. aureus, cell growth of Gram-negative E. coli was not affected by thymol-invasomes.…”

“…We found our terpenoids-invasomes to be bactericidal against Gram-positive S. aureus, with increasing efficiency from cineol-and camphor-invasomes (moderate bactericidal activity) to thymol-invasomes showing the strongest bactericidal effects. These findings are in line with the commonly reported bactericidal activity of thymol, camphor and cineol [10,12,13]. Interestingly, Mulyaningsih and colleagues reported that exposure of MRSA even to high concentrations of cineol does not inhibit multi-resistant S. aureus.…”

“…In this regard, the major treatment aims of our formulations include a broad spectrum of applications, ranging from mucosal infections in airway diseases to systemic infections such as sepsis. In this direction, we have previously shown that patients with chronic rhinosinusitis have increased levels of S. aureus-containing biofilms in the nose [13]. Growth of S. aureus biofilms on the nasal mucosa could be inhibited by 1,8-cineol.…”

“…The terpenoids menthol and camphor also showed anti-bacterial activity against different bacterial species such as streptococci or mycobacteria [11,12]. Cineol was also recently demonstrated to display antibacterial activities against pathogenic bacteria present in chronic rhinosinusitis such as S. aureus [13]. Despite these promising anti-inflammatory and anti-bacterial properties, pharmaceutical applications of terpenoids against bacterial infection remain challenging due to their poor water solubility and high volatility.…”

New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach

“…Furthermore, both Eucalyptus globulus essential oil and 1,8-cineole prevented biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA) and subsequently the spreading of nosocomial infection. A recent study reports genetic downregulation of biofilm induction in chronic rhinosinusitis by 1,8-cineole with inhibition of relevant microbial pathogens (S. aureus, Escherichia coli, Moraxella catarrhalis) and pro-inflammatory NF-jB target genes at relevant concentrations [70]. This may be of further relevance, since in another study the microbiome profile was assessed by using sequencing of the 16S rRNA gene for the followup of hospitalized patients with acute exacerbated COPD (AECOPD) who did not survive with higher Staphylococcus levels [71].…”