A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity

Abstract

Many infectious diseases are associated with multidrug-resistant (MDR) bacteria residing in biofilms that require high antibiotic concentrations. While oral drug delivery is frequently ineffective, topical treatments have the potential to deliver higher drug concentrations to the infection site while reducing systemic side effects. This study determined the antibiofilm activity of a surgical wound gel loaded with the iron chelator deferiprone (Def) and the heme analogue gallium-protoporphyrin (GaPP), alone and in combination with ciprofloxacin. Activity against MDR Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Acinetobacter johnsonii biofilms was assessed in the colony biofilm and artificial wound model by enumeration of CFU and correlative light/electron microscopy. While Staphylococcus biofilms were equally susceptible to GaPP and Def-GaPP gels (log 10 reduction of 3.8 and 3.7, respectively), the Def-GaPP combination was crucial for significant activity against P. aeruginosa biofilms (log 10 reduction of 1.3 for GaPP and 3.3 for DefGaPP). When Def-GaPP gel was combined with ciprofloxacin, the efficacy exceeded the activity of the individual compounds. Def-GaPP delivered in a surgical wound gel showed significant antibiofilm activity against different MDR strains and could enhance the gel's wound-healing properties. Moreover, Def-GaPP indicated a potentiation of ciprofloxacin. This antibiofilm strategy has potential for clinical utilization as a therapy for topical biofilm-related infections.KEYWORDS antimicrobial combinations, biofilms, drug delivery, iron metabolism M edical treatments for chronic infectious diseases are typically based on oral delivery of high-dose, long-term antibiotic therapies. Despite the risk for emerging antimicrobial resistance and the potential of side effects (e.g., gastrointestinal disorders, neutropenia, nephrotoxicity), there is a lack of suitable alternatives. Depending on the disease nature and localization, topical treatments can deliver high dosages of antimicrobials directly to an infection site while reducing unwanted systemic effects. Higher drug dosages are particularly needed to combat microbial biofilms (1). The ability of bacteria to form biofilms and establish resistance to antibiotics is a major biomedical threat, adding billions of dollars to health care costs worldwide (1-3). Biofilms are responsible for 80% of microbial infections in humans and are a common cause of chronic infections, including chronic wound and chronic sinus infections (4, 5), with increasing tolerance and subtle resistance mechanisms to antibiotic therapies (6-8).

Iron/Heme Metabolism-Targeted Gallium(III) Nanoparticles Are Active against Extracellular and Intracellular Pseudomonas aeruginosa and Acinetobacter baumannii

“…Biofilms have substantial influences on the pathogenesis of human infections by reducing antimicrobial susceptibility and enhancing virulence (43,44). Recently, the Ga(III) porphyrins GaPP and GaMP have been described as potential antibiofilm therapies against P. aeruginosa and A. baumannii (21,24). Here, the effects of and Ga(III) porphyrins and nanoparticles containing them on growth inhibition of biofilms with these two pathogens was studied.…”

Topical Colloidal Silver for the Treatment of Recalcitrant Chronic Rhinosinusitis

“…To date, numerous topical agents have been tested and although some have shown anti-biofilm activity (Chiu et al, 2008 ; Le et al, 2008 ; Alandejani et al, 2009 ; Jardeleza et al, 2011 ; Jervis-Bardy et al, 2012 ; Paramasivan et al, 2014 ; Richter et al, 2016 , 2017a , b ), none have been widely accepted as a treatment option in recalcitrant CRS. Recent evidence suggests that colloidal silver (CS) may be effective against bacterial biofilms.…”

Future topical medications in chronic rhinosinusitis

“…Deferiprone is an accepted oral iron chelator prescribed to treat thalassemia major and gallium‐protoporphyrin is a heme analog with wide‐spectrum antibacterial activity . Richter et al described the antibiofilm and the potent synergistic antimicrobial abilities of deferiprone and gallium‐protoporphyrin (DG) . They found that deferiprone increased expression of iron transporter proteins, thought to enhance gallium‐protoprorphyrin IX uptake into bacteria, consequently augmenting bactericidal efficacy.…”