Bacterial fitness shapes the population dynamics of antibiotic-resistant and -susceptible bacteria in a model of combined antibiotic and anti-virulence treatment

Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body's natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population would be unlikely to emerge. However, much controversy surrounds this approach with many believing it would not be powerful enough to clear existing infections, restricting its potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention.Comment: Pre-review manuscript. Submitted to Journal of Theoretical Biology, July 21st 201

Controlling stability and transport of magnetic microswimmers by an external field

We investigate the hydrodynamic stability and transport of magnetic microswimmers in an external field using a kinetic theory framework. Combining linear stability analysis and nonlinear 3D continuum simulations, we show that for sufficiently large activity and magnetic field strengths, a homogeneous polar steady state is unstable for both puller and pusher swimmers. This instability is caused by the amplification of anisotropic hydrodynamic interactions due to the external alignment and leads to a partial depolarization and a reduction of the average transport speed of the swimmers in the field direction. Notably, at higher field strengths a reentrant hydrodynamic stability emerges where the homogeneous polar state becomes stable and a transport efficiency identical to that of active particles without hydrodynamic interactions is restored

Intracellular energy variability modulates cellular decision-making capacity

Cells are able to generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. The biologically and medically vital process of a cell assuming a functionally important fate from a range of phenotypic possibilities can be thought of as a cell decision. To make these decisions, a cell relies on energy dependent pathways of signalling and expression. However, energy availability is often overlooked as a modulator of cellular decision-making. As cells can vary dramatically in energy availability, this limits our knowledge of how this key biological axis affects cell behaviour. Here, we consider the energy dependence of a highly generalisable decision-making regulatory network, and show that energy variability changes the sets of decisions a cell can make and the ease with which they can be made. Increasing intracellular energy levels can increase the number of stable phenotypes it can generate, corresponding to increased decision-making capacity. For this decision-making architecture, a cell with intracellular energy below a threshold is limited to a singular phenotype, potentially forcing the adoption of a specific cell fate. We suggest that common energetic differences between cells may explain some of the observed variability in cellular decision-making, and demonstrate the importance of considering energy levels in several diverse biological decision-making phenomena

Dynamic Monte Carlo Simulations of Anisotropic Colloids

We put forward a simple procedure for extracting dynamical information from Monte Carlo simulations, by appropriate matching of the short-time diffusion tensor with its infinite-dilution limit counterpart, which is supposed to be known. This approach --discarding hydrodynamics interactions-- first allows us to improve the efficiency of previous Dynamic Monte Carlo algorithms for spherical Brownian particles. In a second step, we address the case of anisotropic colloids with orientational degrees of freedom. As an illustration, we present a detailed study of the dynamics of thin platelets, with emphasis on long-time diffusion and orientational correlations.Comment: 12 pages, 9 figure

Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression

Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.publishedVersio

Effects of inertia on conformation and dynamics of active filaments

Many macroscopic active systems such as snakes, birds and fishes have flexible shapes and inertial effects on their motion, in contrast to their microscopic counterparts, cannot be ignored. Nonetheless, the consequences of interplay between inertia and flexibility on their shapes and dynamics remain unexplored. Here, we examine inertial effects on the most studied active flexible system, {\it i.e.} linear active filaments pertinent to worms, snakes and filamentous robots. Performing Langevin dynamics simulations of active polymers with underdamped and overdamped dynamics for a wide range of contour lengths and activities, we uncover striking inertial effects on their conformation and dynamics. Inertial collisions increase the persistence length of active polymers and remarkably alter their scaling behavior. In stark contrast to passive polymers, inertia leaves its fingerprint at long times by an enhanced diffusion of the center of mass. We rationalize inertia-induced enhanced dynamics by analytical calculations of center of mass velocity correlations, revealing significant contributions from active force fluctuations convoluted by inertial relaxation.Comment: 5 pages, 4 figure

Active motion of tangentially driven polymers in periodic array of obstacles

One key question about transport of active polymers within crowded environments is how spatial order of obstacles influences their conformation and dynamics when compared to disordered media. To this end, we computationally investigate the active transport of tangentially driven polymers with varying degrees of flexibility and activity in two-dimensional square lattices of obstacles. Tight periodic confinement induces notable conformational changes and distinct modes of transport for flexible and stiff active filaments. It leads to caging of low activity flexible polymers inside the inter-obstacle pores while promoting more elongated conformations and enhanced diffusion for stiff polymers at low to moderate activity levels. The migration of flexible active polymers occurs via hopping events, where they unfold to move from one cage to another, similar to their transport in disordered media. However, in ordered media, polymers are more compact and their long-time dynamics is significantly slower. In contrast, stiff chains travel mainly in straight paths within periodic inter-obstacle channels while occasionally changing their direction of motion. This mode of transport is unique to periodic environment and leads to more extended conformation and substantially enhanced long-time dynamics of stiff filaments with low to moderate activity levels compared to disordered media. At high active forces, polymers overcome confinement effects and move through inter-obstacle pores just as swiftly as in open spaces, regardless of the spatial arrangement of obstacles. We explain the center of mass dynamics of semiflexible polymers in terms of active force and obstacle packing fraction by developing an approximate analytical theory