Use of ceragenins as a potential treatment for urinary tract infections

Abstract

Background Urinary tract infections (UTIs) are one of the most common bacterial infections. High recurrence rates and the increasing antibiotic resistance among uropathogens constitute a large social and economic problem in current public health. We assumed that combination of treatment that includes the administration ceragenins (CSAs), will reinforce the effect of antimicrobial LL-37 peptide continuously produced by urinary tract epithelial cells. Such treatment might be an innovative approach to enhance innate antibacterial activity against multidrug-resistant E. coli . Methods Antibacterial activity measured using killing assays. Biofilm formation was assessed using crystal violet staining. Viability of bacteria and bladder epithelial cells subjected to incubation with tested agents was determined using MTT assays. We investigated the effects of chosen molecules, both alone and in combinations against four clinical strains of E. coli, obtained from patients diagnosed with recurrent UTI. Results We observed that the LL-37 peptide, whose concentration increases at sites of urinary infection, exerts increased bactericidal effect against E. coli when combined with ceragenins CSA-13 and CSA-131. Conclusion We suggest that the employment of combination of natural peptide LL-37 with synthetic analogs might be a potential solution to treat urinary tract infections caused by drug-resistant bacteria.

<p>NDM-1 Carbapenemase-Producing Enterobacteriaceae are Highly Susceptible to Ceragenins CSA-13, CSA-44, and CSA-131</p>

“…Interestingly, these compounds can be useful in preventing biofilm formation by P. aeruginosa, E. coli (associated with UTI), or Streptococcus pneumoniae. 16,25,42 Additionally, the ability of CSAs to modulate mixed species biofilms formed by organisms like P. aeruginosa and S. aureus or C. albicans and S. aureus was observed. 37,43 Additionally, Durnaś et al 19, demonstrated the significant inhibition of biofilm generation by fungi as C. albicans.…”

“…Accordingly, all ceragenins tested (CSA-13, CSA-44, CSA-131) have been shown to penetrate the extracellular matrix and eradicate a biofilm in a dose-dependent manner. 20,25 Importantly, even non-toxic doses of ceragenins (at least 5-10 μg/mL) inhibit the biofilm formation in the 40-50% range.…”

“…Additionally, pharmacokinetic features of CSA-13 are comparable to conventional antibiotics and might be placed close to fluoroquinolones. 16,23,25,30 In order to check this property of CSAs, hemolysis of RBC was performed. The evaluation of hemoglobin release from RBC can be a helpful clue in determining the potential toxicity of ceragenins.…”

“…[21][22][23][24] The therapeutic potential of CSAs is also underlined by their low toxicity, good stability under physiological conditions, and relatively inexpensive production. 20,25 Because of promising therapeutic properties of CSAs, we investigated antibacterial features of CSA-13, CSA-44, and CSA-131 against rods belonging to Enterobacteriaceae family producing NDM-1.…”

Clinical Pharmacists in Chronic Care

“…Substantial efforts have been expended in development of endogenous antimicrobial peptides (AMPs) as new therapeutic options suitable in the treatment of drug-resistant microbial infections. For example, Wnorowska et.al, 2019 reported that combination of natural peptide LL-37 with synthetic analogs might be a potential solution to treat UTIs caused by drug-resistant bacteria [318]. UTI is one of the most prevalent diseases with diverse etiological agents annually affecting 250 million and causes death of 150 million people overall.…”