Eradicating Cystic Fibrosis Biofilms by a Novel Non-Toxic, Multi-Pathway Salicylate Therapy
1.1. Cystic Fibrosis Biofilms Biofilms are bacterial aggregates in a matrix of polysaccharides, proteins and nucleic acids (Donlan, 2002). They account for 80% of all chronic infections and cause over 500,000 deaths annually. Cystic fibrosis (CF) is a genetic disorder characterized by mucus accumulation in the respiratory tracts (Morrison et al., 2020). This impairs mucociliary clearance, allowing chronic colonization by bacterial biofilms, leading to fatal respiratory failure, lung scarring, and necrosis of pulmonary epithelial tissues (Martin et al., 2021). 1.2. Obstacles in Current Treatments Three major therapies are used against CF biofilms: (1) aminoglycoside antibiotics like tobramycin, (2)non-aminoglycoside antibiotics such as ciprofloxacin and vancomycin, and (3) non-antibiotic therapies including flushing, chlorination, and ultraviolet disinfection. These have two major flaws. First, they are cytotoxic; 30% of patients experience acute kidney injury after three days of intravenous aminoglycoside therapy (Joyce et al., 2017). Furthermore, non-aminoglycoside therapies can cause phospholipid buildup in lysosomes of proximal tubule epithelial cells, accounting for 10-20% of acute renal failure cases. Second, antibiotic resistance due to horizontal gene transfer and mutations has significantly reduced treatment effectiveness. Therefore, cystic fibrosis biofilms remain a critical threat with few effective treatments. 1.3. Salicylate Derivatives This project tackled this issue using an innovative non-antibiotic approach with salicylate derivatives. Salicylates, a class of benzoic acids—benzene-based carboxylic acids (Figure 1)—used in painkillers and blood thinners, were investigated for their antibiofilm potential through a 3-step process: 1. Literature review: Identified three key biofilm therapeutic targets: quorum sensing, bacterial adhesion, and cell motility. Disrupting these pathways would result in biofilm eradication. 2. Molecule Identification: Recognized key molecules in each pathway: LasR, adhesins, and flagellin. Inhibiting these molecules would disrupt the pathways. 3. Screening: Found that salicylates could inhibit the identified molecules, though they had never been tested against cystic fibrosis biofilms.