The Physics of Antimicrobial Resistance

Our objectives

Anti-Microbial resistance (AMR) is one of the most pressing global challenges for humankind. A breakthrough in tackling AMR requires integration of physics and biology. Physics has a crucial role to play since, with multiple time and spatial scales involved, AMR is an emergent property of a complex system. We propose a collaborative, interdisciplinary research programme to address this key challenge which lies at the interface of physics and the life sciences.

The core goal is to determine how resistant bacteria are physically and physiologically different from sensitive ones. The tight integration of physics and biology approaches will enable bridging of scales from molecular to system allowing us to propose mechanistic models, and hence reveal vulnerabilities that can be better exploited to target resistant bacteria. We will concentrate our efforts on the important human pathogens Staphylococcus aureus and Escherichia coli and on resistance to the clinically most important cell wall targeting antibiotics.

Our specific questions and objectives are:

• What are the physical properties of AMR? We will measure and model how the cell envelope is physically different between resistant and sensitive strains. This requires new techniques based on AFM to interrogate the properties of the cell wall and will be combined with the development of new mechanical models and in vitro measurements of peptidoglycan synthesis for wildtype and resistant enzymes.

• What are the physiological changes associated with AMR? We will quantitatively probe the physiological differences between resistant and sensitive strains, in particular the global gene and biochemical regulation that arises from cell crowding and chromosome compaction. This will combine with biochemical measurements of transcription using RNA polymerase from resistant strains. This requires new biophysical tools to grow and image the bacterial species with high throughput and single cell resolution.

• What is the fitness cost of AMR? We will quantify how resistance impacts fitness under different environmental conditions, and how we can exploit these changes in the design of treatment regimens. We can then predict vulnerabilities of AMR bacteria using statistical physics modelling, test them against high throughput growth measurements, and verify these in in vivo models including live in-situ microscopy.

By building collaboration at the physics of life interface, we will provide a breakthrough in our understanding of this global societal challenge that will help ameliorate its impact in the future.

Professor Jamie Hobbs - Principal Investigator, Department of Physics & Astronomy, University of Sheffield