A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance

• DOI: 10.1038/s41467-022-30967-4
• Publication Date: 2022-06-07T10:05:32Z
• Authors: Dmitry Leshchiner; Federico Rosconi; Bharathi Sundaresh; Emily Rudmann; Luisa Maria Nieto...; Andrew T. Nishimoto; Stephen J. Wood; Bimal Jana; Noemí Buján; Kaicheng Li; Jianmin Gao; Matthew Frank; Stephanie M. Reeve; Richard E. Lee; Charles O. Rock; Jason W. Rosch; Tim van Opijnen
• Keywords: 0303 health sciences; 03 medical and health sciences; Streptococcus pneumoniae; Science; Q; Humans; Drug Resistance, Microbial; Drug Tolerance; Microbial Sensitivity Tests; Article; Anti-Bacterial Agents; 3. Good health

Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics diagnostics. It is thereby key to a comprehensive genome-wide understanding of process antibiotic stress, modulation the involved processes affects their ability overcome said stress. Here we undertake genetic analysis human pathogen Streptococcus pneumoniae responds 20 antibiotics. We build atlas drug susceptibility determinants generated interaction network that connects cellular genes unknown function, which show can be used as therapeutic targets. Pathway reveals make bacterium less susceptible, often tolerant, in an specific manner. Importantly, these confers fitness benefits during active infections under selection. Moreover, screening sequenced clinical isolates demonstrates mutations decrease sensitivity increase tolerance readily evolve are frequently associated with resistant strains, indicating such harbingers emergence resistance.