Kinetic Fingerprinting Links Bacteria-Phage Interactions with Emergent Dynamics: Rapid Depletion of Klebsiella pneumoniae Indicates Phage Synergy.

Holger Loessner,Cornelia Pokalyuk,Oleg Krut,Marie Anders-Maurer,Insea Schlattmeier,Christel Kamp,Johannes Wittmann,Christine Rohde,Isabelle Bekeredjian-Ding

doi:10.3390/antibiotics9070408

Abstract

The specific temporal evolution of bacterial and phage population sizes, in particular bacterial depletion and the emergence of a resistant bacterial population, can be seen as a kinetic fingerprint that depends on the manifold interactions of the specific phage–host pair during the course of infection. We have elaborated such a kinetic fingerprint for a human urinary tract Klebsiella pneumoniae isolate and its phage vB_KpnP_Lessing by a modeling approach based on data from in vitro co-culture. We found a faster depletion of the initially sensitive bacterial population than expected from simple mass action kinetics. A possible explanation for the rapid decline of the bacterial population is a synergistic interaction of phages which can be a favorable feature for phage therapies. In addition to this interaction characteristic, analysis of the kinetic fingerprint of this bacteria and phage combination revealed several relevant aspects of their population dynamics: A reduction of the bacterial concentration can be achieved only at high multiplicity of infection whereas bacterial extinction is hardly accomplished. Furthermore the binding affinity of the phage to bacteria is identified as one of the most crucial parameters for the reduction of the bacterial population size. Thus, kinetic fingerprinting can be used to infer phage–host interactions and to explore emergent dynamics which facilitates a rational design of phage therapies.

Highlights

A century after their discovery, phages—viruses that infect bacteria—have regained attention as highly specific anti-microbial agents for the treatment of multidrug-resistant (MDR) bacterial pathogens where common broad-spectrum antibiotic drugs increasingly fail [1,2,3,4]
In order to understand the dynamics of bacterial and phage populations, we further developed an approach based on [14] which allows us to understand the dynamics of bacterial and phage populations in terms of certain thresholds in bacterial and phage population sizes: The proliferation threshold SP defines a minimal bacterial concentration required to support phage proliferation, the inundation threshold VI represents the phage concentration required to deplete a population of sensitive bacteria
These thresholds as well as model parameters are estimated from experimental observations that we gained by adding phage vB_KpnP_Lessing in different multiplicities of infection (MOI) to an early log phase culture of Klebsiella pneumoniae strain DSM 11678

Summary

Introduction

A century after their discovery, phages—viruses that infect bacteria—have regained attention as highly specific anti-microbial agents for the treatment of multidrug-resistant (MDR) bacterial pathogens where common broad-spectrum antibiotic drugs increasingly fail [1,2,3,4]. In order to advance a rational, safe, and efficacious application of phage therapy the characteristics of specific phage–pathogen interactions must be unraveled in order to predict and tailor conditions for the application of therapeutic phages to individual patients. Safety and efficacy of treatment regimens must be proven in clinical trials before phage therapy medicinal products become available for routine use in medical practice [10]

Methods

Results

Conclusion