Adaptation of Enterococcus faecalis to Daptomycin Reveals an Ordered Progression to Resistance

摘要: With increasing numbers of hospital-acquired antibiotic resistant infections each year and staggering health care costs, there is a clear need for new antimicrobial agents, as well novel strategies to extend their clinical efficacy. While genomic studies have provided wealth information about the alleles associated with adaptation antibiotics, they do not provide essential relative importance changes, order appearance, or potential epistatic relationships between adaptive changes. Here we used quantitative experimental evolution single polymorphic population in continuous culture whole-genome sequencing allelic frequency measurements study daptomycin (DAP) resistance vancomycin-resistant pathogen Enterococcus faecalis S613. Importantly, sustained both planktonic nonplanktonic (i.e., biofilm) populations coculture concentration was raised, facilitating development more ecological complexity than typically observed laboratory evolution. Quantitative revealed hierarchy genetic changes leading resistance, signaling metabolic pathways responsible, these mutations DAP resistance. Despite simplicity this ex vivo approach compared human body, showed that allows rapid identification clinically relevant molecular targets drug design pathogens.