The role of tolerance in the evolution of antibiotic resistance: from mathematical analysis to observations in the clinic*

The evolution of antibiotic resistance is a fascinating example of the versatility of bacterial evolution, as well as a burning health issue. Resistance mechanisms include efflux pumps that directly lower the intracellular drug concentration, mutations that reduce binding affinity of the drug to its target, enzymes that degrade the drug, etc. These mechanisms result in a decrease of the effective concentration of the antibiotic. However, bacteria were shown to be able to cope with antibiotic treatments that are supposed to kill them also using a different strategy termed “tolerance”. Tolerant bacteria are not able to reduce the concentration of the antibiotic, but to make the duration of the treatment less effective. For example, bacteria that remain transiently dormant during the antibiotic treatment can survive because many different types of antibiotics require active growth to be able to kill. We developed a mathematical and experimental framework to characterize and measure the evolution of tolerance in vitro(1) and in vivo(2). By following the evolution of tolerance and resistance closely, we show that tolerance evolves fast and promotes the subsequent evolution of resistance. Mathematical analysis of the way tolerance promotes the evolution of resistance reveals unexpected routes by which tolerance acts as a stepping stone for the subsequent evolution of resistance.
(1) Levin-Reisman I. et al., Science 355:826-830 (2017)
(2) Liu Jiafeng et al., Submitted