RT Journal Article
SR Electronic
T1 A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.26.477867
DO 10.1101/2022.01.26.477867
A1 Dmitry Leshchiner
A1 Federico Rosconi
A1 Bharathi Sundaresh
A1 Emily Rudmann
A1 Luisa Maria Nieto Ramirez
A1 Andrew T. Nishimoto
A1 Stephen J. Wood
A1 Bimal Jana
A1 Noemí Buján
A1 Kaiching Li
A1 Jianmin Gao
A1 Matthew Frank
A1 Stephanie M. Reeve
A1 Richard E. Lee
A1 Charles O. Rock
A1 Jason W. Rosch
A1 Tim van Opijnen
YR 2022
UL http://biorxiv.org/content/early/2022/01/26/2022.01.26.477867.abstract
AB Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the major human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We built a genome-wide atlas of drug susceptibility determinants and generate a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide “tolerome”, defined by cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in tolerome genes readily evolve and are frequently associated with resistant strains, indicating such mutations may be an important harbinger for the emergence of antibiotic resistance.Competing Interest StatementThe authors have declared no competing interest.