Background: Staphylococcus aureus is associated with recurring respiratory tract infections, such as chronic rhinosinusitis and cystic fibrosis. S. aureus has the capacity to form biofilms and small colony variants (SCVs), which are pathogenic subpopulations with a preferred intracellular lifestyle. S. aureus biofilms and SCVs are linked to antibiotic tolerance and resistance, and are challenging to eradicate. Despite aggressive antimicrobial therapies and surgery, infections often recur causing ongoing morbidity and significant healthcare costs.
Aim: Preclinical validation of an antibiofilm and anti-SCV treatment targeting bacterial iron metabolism
Methods: The iron-chelator deferiprone (Def) and the haem-analogue gallium-protoporphyrin (GaPP), in solution and incorporated in a surgical wound gel, were tested for antibacterial activity using multidrug-resistant S. aureus SCVs in an intracellular infection model. The antibiofilm activity was assessed in vitro in the colony biofilm model and an artificial wound model, as well as in an in vivo infection model in nematodes (Caenorhabditis elegans).
Results: While Def alone failed to show substantial antibacterial activity, GaPP and the combination of Def-GaPP demonstrated concentration- and strain-dependent antibacterial properties. Specifically, the Def-GaPP combination significantly reduced the bacterial load in an artificial wound model (1.4 log10 reduction) and increased the survival of S. aureus SCV infected nematodes (86% survival of infected, treated worms vs. 25% survival of infected, untreated worms over 3 days). When Def-GaPP were combined with ciprofloxacin (Cip) or gentamicin (Gent), the triple combinations exceeded the antibiofilm activity of the individual compounds in the colony biofilm model against Cip- and Gent-resistant strains (5.4 log10 reduction for Def-GaPP-Cip and 3.4 log10 reduction for Def-GaPP-Gent). Moreover, Def-GaPP-Gent eradicated intracellular SCVs in human bronchial epithelial cells.
Summary: Def-GaPP showed significant activity against S. aureus biofilms and SCVs and potentiated the activity of Cip and Gent against resistant strains. Delivered in a wound healing gel, Def-GaPP progressed to a first-in-human pilot study for the treatment of chronic rhinosinusitis.