Increasing antibiotic resistance and the declining rate at which new antibiotics come into use create a need to increase the efficacy of existing antibiotics. The aminoglycoside tobramycin is standard-of-care for many types of Pseudomonas aeruginosa infections, including those in the lungs of cystic fibrosis (CF) patients. P. aeruginosa is a nosocomial and opportunistic pathogen that, in planktonic form, causes acute infections and, in biofilm form, causes chronic infections. Inhaled bicarbonate has recently been proposed as a therapy to improve antimicrobial properties of the CF airway surface liquid and viscosity of CF mucus. Here we measure the effect of combining tobramycin and bicarbonate against P. aeruginosa, both lab strains and CF clinical isolates. Bicarbonate synergises with tobramycin to enhance killing of planktonic bacteria. In contrast, bicarbonate antagonises with tobramycin to promote better biofilm growth. This suggests caution when evaluating bicarbonate as a therapy for CF lungs infected with P. aeruginosa biofilms. We analyse tobramycin and bicarbonate interactions using an interpolated surface methodology to measure the dose–response function. These surfaces allow more accurate estimation of combinations yielding synergy and antagonism than do standard isobolograms. By incorporating predictions based on Loewe additivity theory, we can consolidate information on a wide range of combinations that produce a complex dose–response surface, into a single number that measures the net effect. This tool thus allows rapid initial estimation of the potential benefit or harm of a therapeutic combination. Software code is freely made available as a resource for the community.

Membrane adhesion is essential to many vital biological processes. Sites of membrane adhesion are often associated with heterogeneities in the lipid and protein composition of the membrane. These heterogeneities are thought to play functional roles by facilitating interactions between proteins. However, the causal links between membrane adhesion and membrane heterogeneities are not known. Here we survey the state of the field and indicate what we think are understudied areas ripe for development.

Membrane adhesion is a vital component of many biological processes. Heterogeneities in lipid and protein composition are often associated with the adhesion site. These heterogeneities are thought to play functional roles in facilitating signalling. Here we experimentally examine this phenomenon using model membranes made of a mixture of lipids that is near a phase boundary at room temperature. Non-adherent model membranes are in a well-mixed, disordered-fluid lipid phase indicated by homogeneous distribution of a fluorescent dye that is a marker for the fluid-disordered (L d ) phase. We specifically adhere membranes to a flat substrate bilayer using biotin-avidin binding. Adhesion produces two types of coexisting heterogeneities: an ordered lipid phase that excludes binding proteins and the fluorescent membrane dye, and a disordered lipid phase that is enriched in both binding proteins and membrane dye compared with the non-adhered portion of the same membrane. Thus, a single type of adhesion interaction (biotin-avidin binding), in an initially-homogeneous system, simultaneously stabilizes both ordered-phase and disordered-phase heterogeneities that are compositionally distinct from the non-adhered portion of the vesicle. These heterogeneities are long-lived and unchanged upon increased temperature.

We present a numerical model to simulate the growth and deformation of a viscoelastic biofilm in shear flow under different nutrient conditions. The mechanical interaction between the biofilm and the fluid is computed using the Immersed Boundary Method with viscoelastic parameters determined a priori from measurements reported in the literature. Biofilm growth occurs at the biofilm-fluid interface by a stochastic rule that depends on the local nutrient concentration. We compare the growth, migration, and morphology of viscoelastic biofilms with a common relaxation time of 18 min over the range of elastic moduli 10–1000 Pa in different nearby nutrient source configurations. Simulations with shear flow and an upstream or a downstream nutrient source indicate that soft biofilms grow more if nutrients are downstream and stiff biofilms grow more if nutrients are upstream. Also, soft biofilms migrate faster than stiff biofilms toward a downstream nutrient source, and although stiff biofilms migrate toward an upstream nutrient source, soft biofilms do not. Simulations without nutrients show that on the time scale of several hours, soft biofilms develop irregular structures at the biofilm-fluid interface, but stiff biofilms deform little. Our results agree with the biophysical principle that biofilms can adapt to their mechanical and chemical environment by modulating their viscoelastic properties. We also compare the behavior of a purely elastic biofilm to a viscoelastic biofilm with the same elastic modulus of 50 Pa. We find that the elastic biofilm underestimates growth rates and downstream migration rates if the nutrient source is downstream, and it overestimates growth rates and upstream migration rates if the nutrient source is upstream. Future modeling can use our comparison to identify errors that can occur by simulating biofilms as purely elastic structures.