Abstract
Here we formulate a mechanistic mathematical model to describe the growth dynamics of P. aeruginosa in the presence of the β-lactam antibiotic meropenem. The model is mechanistic in the sense that carrying capacity is taken into account through the dynamics of nutrient availability rather than via logistic growth. In accordance with our experimental results we incorporate a sub-population of cells, differing in morphology from the normal bacillary shape of P. aeruginosa bacteria, which we assume have immunity from direct antibiotic action. By fitting this model to experimental data we obtain parameter values that give insight into the growth of a bacterial population that includes different cell morphologies. The analysis of two parameters sets, that produce different long term behaviour, allows us to manipulate the system theoretically in order to explore the advantages of a shape transition that may potentially be a mechanism that allows P. aeruginosa to withstand antibiotic effects. Our results suggest that inhibition of this shape transition may be detrimental to bacterial growth and thus suggest that the transition may be a defensive mechanism implemented by bacterial machinery. In addition to this we provide strong theoretical evidence for the potential therapeutic strategy of using antimicrobial peptides (AMPs) in combination with meropenem. This proposed combination therapy exploits the shape transition as AMPs induce cell lysis by forming pores in the cytoplasmic membrane, which becomes exposed in the spherical cells.
Highlights
Antimicrobial resistance (AMR) is acknowledged as an urgent global health threat and the severity of the situation was highlighted by the World Health Organization 2014 report that discusses the increasing incidence of resistance-induced health problems in every region of the world [1]
Antimicrobial resistance is an urgent global health threat and it is critical that we formulate alternative treatment strategies to combat bacterial infections
A sample from each flask was normalised to an optical density at 600 nm (OD600) of 1 by centrifuging the sample and re-suspending in the appropriate volume of PBS. 500μl of each sample was stained with 1.5μl of LIVE/DEAD BacLight stain mixture and incubated for 15 minutes at room temperature, in the dark
Summary
Antimicrobial resistance (AMR) is acknowledged as an urgent global health threat and the severity of the situation was highlighted by the World Health Organization 2014 report that discusses the increasing incidence of resistance-induced health problems in every region of the world [1]. It is imperative that we try to gain a deeper understanding of currently used drug treatments and the mechanism of action of a drug and the consequential response of a bacterial population. Elucidating the mechanistic interactions between bacteria and antibiotic increases our understanding of how pathogens react in response to antimicrobials and the concurrent impact on the selective pressure that can influence the emergence of resistance. A popular strategy used to investigate mechanisms of action is the examination of the morphology of treated bacteria. This is a relatively simple experimental procedure that can be used as an initial preliminary step in an investigation or to provide further evidence to support a suspected mechanistic interaction
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