Antibiotic resistance increases evolvability and maximizes opportunities across fitness landscapes

Antibiotic resistance continues to grow as a public health problem. One of the reasons for this continued growth is that resistance to antibiotics is strongly selected for in the presence of antibiotics and weakly selected against after their removal. This is frequently thought to be due to the effects of compensatory mutations. However, compensatory mutations are often not found in clinically relevant strains of antibiotic resistant pathogens. Here, we conduct experiments in vitro using chemostats and serial transfer flasks that highlight the role that fine scale differences in environment play in the maintenance of populations after selection for resistance. Chemostat conditions resulted in a different set of mutations than in flasks, showing that the differences in the mode of growth are capable of reliably changing the force and direction of selection. Our results suggest that antibiotic resistance can make novel adaptive paths available to populations through newly arising variation, allowing populations to climb previously unavailable adaptive peaks in a manner similar to Wright's shifting balance, but driven only by selection.