Modeling the response of a biofilm to silver-based antimicrobial.

Biofilms are found within the lungs of patients with chronic pulmonary infections, in particular patients with cystic fibrosis, and are the major cause of morbidity and mortality for these patients. The work presented here is part of a large interdisciplinary effort to develop an effective drug delivery system and treatment strategy to kill biofilms growing in the lung. The treatment strategy exploits silver-based antimicrobials, in particular, silver carbene complexes (SCC). This manuscript presents a mathematical model describing the growth of a biofilm and predicts the response of a biofilm to several basic treatment strategies. The continuum model is composed of a set of reaction-diffusion equations for the transport of soluble components (nutrient and antimicrobial), coupled to a set of reaction-advection equations for the particulate components (living, inert, and persister bacteria, extracellular polymeric substance, and void). We explore the efficacy of delivering SCC both in an aqueous solution and in biodegradable polymer nanoparticles. Minimum bactericidal concentration (MBC) levels of antimicrobial in both free and nanoparticle-encapsulated forms are estimated. Antimicrobial treatment demonstrates a biphasic killing phenomenon, where the active bacterial population is killed quickly followed by a slower killing rate, which indicates the presence of a persister population. Finally, our results suggest that a biofilm with a ready supply of nutrient throughout its depth has fewer persister bacteria and hence may be easier to treat than one with less nutrient.

Nanoparticle deposition onto biofilms.

We develop a mathematical model of nanoparticles depositing onto and penetrating into a biofilm grown in a parallel-plate flow cell. We carry out deposition experiments in a flow cell to support the modeling. The modeling and the experiments are motivated by the potential use of polymer nanoparticles as part of a treatment strategy for killing biofilms infecting the deep passages in the lungs. In the experiments and model, a fluid carrying polymer nanoparticles is injected into a parallel-plate flow cell in which a biofilm has grown over the bottom plate. The model consists of a system of transport equations describing the deposition and diffusion of nanoparticles. Standard asymptotic techniques that exploit the aspect ratio of the flow cell are applied to reduce the model to two coupled partial differential equations. We perform numerical simulations using the reduced model. We compare the experimental observations with the simulation results to estimate the nanoparticle sticking coefficient and the diffusion coefficient of the nanoparticles in the biofilm. The distributions of nanoparticles through the thickness of the biofilm are consistent with diffusive transport, and uniform distributions through the thickness are achieved in about four hours. Nanoparticle deposition does not appear to be strongly influenced by the flow rate in the cell for the low flow rates considered.

Structure and conformation of DAB dendrimers in solution via multidimensional NMR techniques.

NOESY-HSQC 3D-NMR and NOESY 2D-NMR techniques have been used on a 750 MHz spectrometer to study the chain conformations of different generation DAB dendrimers (poly[propylene imine] dendrimers) in chloroform and benzene solutions. The high-field multidimensional NMR techniques provided the chemical shift dispersion needed to resolve all of the unique resonances in the dendrimers. By studying the NOE interactions among dendritic chain protons, information about through space interactions between protons on different parts of the dendrimer chain is obtained, which is directly related to the conformation of the dendrimer. These experiments also give further proof of the chemical shift assignments obtained from the HMQC-TOCSY 2D and 3D NMR experiments. The concentration effects on chemical shifts have also been observed, revealing information about the interactions between solvent and different parts of dendrimer molecules. These studies clearly show for DAB dendrimers, that folded chain conformations can occur in nonpolar solvents such as benzene and extended chain conformations are predominant in polar solvents such as chloroform.

Synthesis and structural characterization of a silver complex of a mixed-donor N-heterocyclic carbene linked cyclophane.

The synthesis of a dicationic imidazolium-linked cyclophane and a dimeric silver-N-heterocyclic carbene complex, that is the first silver complex with a N-heterocyclic carbene ligand involved in a pi-bonding interaction, is reported.