Evolution of resistance to RNA polymerase-targeting antibiotics

Antibiotics are medicines used to prevent and treat bacterial infections. Antibiotic resistance occurs when bacteria evolve in response to the use of these medicines, which decreases the effectiveness of the antibiotics to control infections. Resistance leads to prolonged hospital stays and increased mortality rates. The UK government and other important health organizations, such as WHO, understand and support the need to change the way antibiotics are used and prescribed globally. Without this urgent action, we are heading toward “a post-antibiotic era”, in which common infections and minor injuries can once again kill.

Tackling this problem requires drastically improving our ability to predict antibiotic resistance evolution. One of the major parameters required to predict evolution is being able to predict the effects of new mutations on organismal fitness – a goal that has largely eluded evolutionary biologists. Gaining the ability to do so requires understanding how the structures of molecules targeted by antibiotics change when they acquire resistance mutations, and how those changes, in turn, affect the propensity to evolve resistance to further antibiotics. This is particularly important when considering bacteria that carry resistance to multiple antibiotics as a consequence of having been exposed to several drugs sequentially.

This project will focus on one of the largest families of antibiotics – those that target RNA polymerase, the complex molecule responsible for transcribing DNA into RNA. Resistance to these drugs often occurs through mutations in the RNA polymerase genes rpoB and rpoC. These mutations prevent the drug from binding, but also alter the structure and function of the molecule. What remains poorly understood is how one resistance mutation alters the evolution of resistance to other antibiotics? In other words, one mutation changes the structure of RNA polymerase, and that change in structure can alter the propensity of the molecule to acquire other resistance mutations. This PhD project will understand that interaction between structure and the propensity to evolve resistance at a mechanistic level, improving our ability to predict antibiotic resistance evolution.

In order to ensure that the predictive understanding of rpoB and rpoC evolution is actually observed in clinical settings, a major part of the project will focus on population health: analysis of antibiotic resistant bacterial strains isolated from patients. The student will determine the mechanisms of resistance observed in these strains, and further evolve them in the lab in order to test the accuracy of our predictions of evolution.

The project is highly interdisciplinary, combining molecular, structural and evolutionary biology with modelling and population health. It provides a unique opportunity to work in three different groups with diverse set of expertise, on a problem of great societal relevance.

Supervisors:
Professor Benjamin Howden, Faculty of Medicine, Dentistry and Health Sciences (Doherty Institute), The University of Melbourne

Dr Mato Lagator, The University of Manchester