Heteroresistance: mechanisms, clinical relevance and diagnostics

Understanding resistance mechanisms is critical to designing novel approaches, therapeutics and diagnostics to combat resistant bacteria.

Heteroresistance (HR) is a form of antibiotic resistance characterized by the presence of small resistant subpopulation(s), in a main population of susceptible cells.

During antibiotic exposure the resistant cells can rise to high frequency and cause treatment failure/recurrent infections.

Not only do many species of bacteria exhibit this form of resistance, but it has been reported against most antibiotic classes.

A general mechanism for HR involves spontaneous tandem gene amplification of resistance-conferring genes in a subpopulation of cells.

Since gene amplifications are unstable and present at low frequency in the population, the resistant subpopulations are difficult to detect and study, leading to difficulties in classifying bacteria as susceptible or resistant in clinical settings.

In this project, we will examine if copy number variation is a universal explanation for HR in several bacterial pathogens, the dynamics of the gene amplifications and the clinical impact of such mechanisms on treatment outcome and diagnostics.

By performing these studies in several bacterial species of high relevance with regard to infectious diseases (both Gram+ and Gram), including genetically amenable bacteria such as E. coli, we will obtain a comprehensive picture of genotype—phenotype correlations and the genetics and physiology underlying HR.