Genetic determinants of antibiotic resistance and the evolution of trade-offs during adaptation in a single patient

Abstract

The processes by which pathogens evolve within single hosts dictate the efficacy of treatment strategies designed to slow antibiotic resistance evolution and influence the population-wide resistance levels. The aim of this study is to describe the underlying genetic and phenotypic changes leading to antibiotic resistance within a single patient who died as resistance evolved to available antibiotics. We assess whether robust patterns of collateral sensitivity and response to combinations exist that might have been leveraged to improve therapy. Whole-genome sequencing was completed for nine isolates taken from this patient over 279 days of chronic infection with Enterobacter hormaechei, along with systematic measurements of changes in resistance against five of the most relevant drugs considered for treatment. The entirety of the genetic change is consistent with de novo mutations and plasmid loss events, without the acquisition of foreign genetic material via horizontal gene transfer. The isolates formed three genetically distinct lineages, with early evolutionary trajectories being supplanted by previously unobserved multi-step evolutionary trajectories. Importantly, no single isolate evolved resistance to all of the antibiotics considered for treatment against E. hormaechei (i.e., none was pan-resistant). Patterns of collateral sensitivity and response to combination therapy revealed contrasting patterns across this diversifying population. Translating antibiotic resistance management strategies from theoretical and laboratory data to clinical situations, such as this, may require managing diverse populations with unpredictable resistance trajectories.