Transforming biofilm treatments in urinary tract infections: targeting specialised arsenal of uropathogens using N-acetylcysteine

Abstract

Urinary tract infections (UTIs) affect >150 million individuals annually and are associated with soaring rates of antibiotic resistance, primarily due to poor biofilm eradication. Biofilms on catheters and in the bladder form bacterial reservoirs that cannot be eradicated by antibiotics alone. In catheter (CA)-UTIs, infected catheters are replaced, but get rapidly recolonised by an existing infection. Thus, alternative approaches are required to treat UTIs.

N-acetyl cysteine (NAC) is a thiol antioxidant previously investigated for its antibiofilm properties. This research examines the antibiofilm effect of NAC, alone and combined with ciprofloxacin, on clinical isolates of key uropathogens. NAC and NAC +ciprofloxacin drastically reduced biofilm viability across four UTI species and significantly inhibited bladder epithelial cell (BEC) invasion. Moreover, NAC was determined to be nontoxic to BECs at intrinsically low pH, thus substantiating the use of NAC in the urinary tract.

Next, using a glass bladder model, we determined that NAC completely prevented catheter blockage in P. mirabilis infection. This corroborated a concurrent finding that NAC is a powerful inhibitor of P. mirabilis urease. We also demonstrated that NAC treatment can prevent extensive catheter encrustation by P. aeruginosa biofilms. Finally, we observed that NAC significantly limited inflammation (IL-6, IL-8, IL-1b) and oxidative stress in response to infection, urease and pyocyanin. This anti-inflammatory effect is paramount for maintaining bladder barrier integrity to resist UTIs.

Ultimately, we have defined the role of NAC in preventing biofilm formation, bacterial invasion of BECs and inhibiting urease. These results can better inform using NAC as an efficacious strategy in treating biofilm formation in catheters and the bladder epithelium. Combining NAC +antibiotic provides a two-pronged approach to eliminate residual bacteria in UTIs,thus potentially preventing recurrence and drug resistance.