Predicting cell-cell horizontal transmission of antibiotics resistance from genome and phenome

We propose to disclose candidate drug targets controlling the horizontal cell-cell transmission of anti-microbial resistance (AMR) and to predict AMR and its transmission dynamics from bacterial genome composition. We will integrate leading expertise from bacteriology, -omics and mathematical biology in the development of an integrated theoretical-empirical framework of plasmid borne transmission of AMR cassettes. We will employ massive-scale experimental evolution of Escherichia coli and Salmonella enterica gene deletion and overexpression collections, where adaptation requires transfer of AMR carrying conjugative plasmids. In addition, we will select for, identify and functionally dissect de novo mutations that promote horizontal transmission during long-term experimental evolution. Both approaches will disclose cellular functions controlling horizontal AMR transmission that are candidate targets for helper drugs delaying AMR development and spread. Second, we will sequence vast swaths of the genotype space inhabited by clinical bacterial isolates and disclose variants likely to alter transmission properties. DNA sequence data will be complemented by data on transcriptome, proteome and antibiotics resistance, allowing causally cohesive reconstruction of the history of antibiotics resistance. Third, we will integrate the omics data into a mathematical framework capable of predicting AMR transmission in clinical isolates, thereby laying the foundations for a future personalized medicine that tailors antibiotic choice to infection.

We propose to disclose candidate drug targets controlling the horizontal cell-cell
transmission of anti-microbial resistance (AMR) and to predict AMR and its transmission
dynamics from bacterial genome composition. We will integrate leading expertise from
bacteriology, -omics and mathematical biology in the development of an integrated
theoretical-empirical framework of plasmid borne transmission of AMR cassettes. We will
employ massive-scale experimental evolution of Escherichia coli and Salmonella enterica
gene deletion and overexpression collections, where adaptation requires transfer of AMR
carrying conjugative plasmids. In addition, we will select for, identify and functionally dissect
de novo mutations that promote horizontal transmission during long-term experimental
evolution. Both approaches will disclose cellular functions controlling horizontal AMR
transmission that are candidate targets for helper drugs delaying AMR development and
spread. Second, we will sequence vast swaths of the genotype space inhabited by clinical
bacterial isolates and disclose variants likely to alter transmission properties. DNA sequence
data will be complemented by data on transcriptome, proteome and antibiotics resistance,
allowing causally cohesive reconstruction of the history of antibiotics resistance. Third, we
will integrate the omics data into a mathematical framework capable of predicting AMR
transmission in clinical isolates, thereby laying the foundations for a future personalized
medicine that tailors antibiotic choice to infection.

The Center for AMR (CARe; http://care.gu.se/) at
University of Gothenburg (partners 1 and 2 are core members) provides an overall context
within which we will manage the project and communicate with industry, regulatory bodies
and patient organizations. CARe have direct channels to international and national
regulatory bodies, interacts with commercial actors on both the drug development and
diagnostics side and has well established interfaces with patient organizations such as
REACT (http://www.reactgroup.org/) on the international level and its Nordic (NordicAST;
http://www.nordicast.org/) and Swedish subsidiaries (STRAMA;
http://www.reactgroup.org/toolbox/the-swedish-strama-program-2/).
* To exploit the mathematical framework for predicting the spread of antibiotics
resistance (WP4), we will interact closely with 1928 diagnostics
(http://www.1928diagnostics.com/) and Nanoxis consulting
(http://nanoxisconsulting.com/). This is outlined in section 14.
* To exploit emerging candidate drug targets controlling horizontal transmission (WP1,
WP2), we will interact with medicinal and organic chemists within the Centre for
Antibiotics Resistance rEsearch (CARe). Partner 1 is deeply involved in setting-up a
research centre for the development of long-lasting antibiotics (DLLA) at the
University of Gothenburg. This centre will become central in proceeding from
candidate drug targets to candidate drugs. We also expect to hold explorative
discussions with EU-OPENSCREEN, EATRIS and ENABLE, as outlined in section
JPI-EC-AMR JTC 2016 Full-proposal application form