Tandem 4: The evolution of human pathogens under antibiotic therapy

Background - Pathogenic microorganisms have shaped human history through repeated epidemics and pandemics, causing enormous mortality rates. The discovery of antibiotics in the 20th century thus represented a major breakthrough, massively reducing otherwise fatal bacterial infections. Yet, the application of these drugs immediately led to the spread of antibiotic resistance. Especially the intensive use of antibiotics in humans, but also in animal husbandry and generally food production during the last decades favored multi-drug resistant pathogens that are often difficult, and in some cases impossible to treat. Evolution is at the core of the current situation. Any sustainable treatment strategy must thus take into account the enormous potential of pathogens to adapt to novel drug environments. This potential can be assessed by studying the history of pathogen adaptation using clinical pathogen isolates from patients with documented health characteristics and antibiotic treatment (e.g., phylogenomic analysis of Mycobacterium tuberculosis complex (Mtbc)). An alternative approach is the performance of highly controlled laboratory evolution experiments (e.g., experiments of alternative treatment protocols with the human pathogen Pseudomonas aeruginosa). Sequential therapy holds particular promise if two drugs that show reciprocal collateral sensitivity are alternated. This concept implies that evolution of resistance to one drug causes susceptibility towards a second drug. Its clinical potential is as yet unclear.

Overall objectives

  • Determine the efficacy of novel treatment strategies such as sequential protocols to reduce resistance evolution in clinical pathogen isolates
  • Identify evolutionary trade-offs and associated molecular genetic mechanisms that influence the efficacy of antibiotic treatment protocols
  • Evaluate to what extent pathogen adaptation to antibiotics under laboratory conditions reflects evolution of clinical pathogen isolates
  • Assess which other factors (e.g., human immune status, strain genetic background and diversity) influence pathogen adaptation to antibiotics

Doctoral project 4.1: Adaptation of Mtbc to antibiotic treatment

Specific aims

  • Identify potential low level resistance mutations associated with a stepwise increase in resistance against particular antibiotics and identify associated evolutionary trade-offs
  • Quantify fitness enhancing mutations that are suggested to contribute to the emergence of large multi-drug resistance Mtbc transmission networks
  • Define mutation rates in different physiological conditions (e.g. hypoxia)
  • Test alternative treatment protocols for Mtbc

People working on this project

  • Prof. Dr. Stefan Niemann
  • Dr. Matthias Merker
  • MSc Emilie Rousseau

PI's Homepage: https://fz-borstel.de/index.php/en/sitemap/priority-research-area-infections-prof-dr-ulrich-schaible/molecular-and-experimental-mycobacteriology-prof-dr-stefan-niemann/staff

Doctoral project 4.2: Efficacy of sequential therapy against clinical Pseudomonas

Specific aims

  • Use evolution experiments for testing the efficacy of sequential treatment protocols with Pseudomonas aeruginosa
  • Identify trait functions under selection during alternative antibiotic therapies using phenotypic assays and genome sequencing of experimentally evolved bacteria
  • Compare phenotypic and genomic evolutionary responses to antibiotic treatment among experimentally evolved and clinical isolates of Pseudomonas aeruginosa

People working on this project

  • Prof. Dr. Hinrich Schulenburg
  • MSc Florian Henkies

PI's Homepage: http://www.uni-kiel.de/zoologie/evoecogen/