Abstract
Due to the intrinsic resistance of Burkholderia cepacia complex (Bcc) to many antibiotics and the production of a broad range of virulence factors, lung infections by these bacteria, primarily occurring in cystic fibrosis (CF) patients, are very difficult to treat. In addition, the ability of Bcc organisms to form biofilms contributes to their persistence in the CF lung. As Bcc infections are associated with poor clinical outcome, there is an urgent need for new effective therapies to treat these infections. In the present study, we investigated whether liposomal tobramycin displayed an increased anti-biofilm effect against Bcc bacteria compared to free tobramycin. Single particle tracking (SPT) was used to study the transport of positively and negatively charged nanospheres in Bcc biofilms as a model for the transport of liposomes. Negatively charged nanospheres became immobilized in close proximity of biofilm cell clusters, while positively charged nanospheres interacted with fiber-like structures, probably eDNA. Based on these data, encapsulation of tobramycin in negatively charged liposomes appeared promising for targeted drug delivery. However, the anti-biofilm effect of tobramycin encapsulated into neutral or anionic liposomes did not increase compared to that of free tobramycin. Probably, the fusion of the anionic liposomes with the negatively charged bacterial surface of Bcc bacteria was limited by electrostatic repulsive forces. The lack of a substantial anti-biofilm effect of tobramycin encapsulated in neutral liposomes could be further investigated by increasing the liposomal tobramycin concentration. However, this was hampered by the low encapsulation efficiency of tobramycin in these liposomes.
Highlights
Cystic fibrosis (CF) is the most prevalent hereditary disease in the Caucasian population and is caused by mutations in both cftr alleles encoding a chloride channel [1]
It has been shown that subinhibitory concentrations of tobramycin encapsulated in neutral liposomes displays a high bactericidal activity against planktonic cultures of several bacterial species, including P. aeruginosa and B. cenocepacia [16,17,18], probably due to an enhanced uptake of the antibiotic
Negatively charged particles display subdiffusion (0,a,1 ) when added to the biofilm. This most pronounced subdiffusion is observed in B. cenocepacia LMG 16656 and B. cenocepacia LMG 18829 biofilms and to a lesser extent in B. multivorans LMG 18825 and B. cepacia LMG 1222 biofilms
Summary
Cystic fibrosis (CF) is the most prevalent hereditary disease in the Caucasian population and is caused by mutations in both cftr alleles encoding a chloride channel [1]. Liposome-encapsulated antibiotics are protected from degradation by antibiotic-inactivating enzymes (like b-lactamases) which can accumulate in the biofilm matrix [11] Another important factor contributing to antibiotic resistance in several Gram-negative bacteria, including P. aeruginosa and Bcc species, is their low outer membrane permeability [12,13,14]. A neutral liposomal amikacin formulation, currently undergoes phase III clinical trials for the treatment of lung infections [19,20]. It is the first liposomal drug being investigated for aerosol delivery
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