The Role of Compensatory Mutations in the Emergence of Drug Resistance
Figure 2
The Process of Resistance Emergence
The bars indicate between-host fitness levels of the different strains. Solid curved arrows show conversion events that occur frequently due to large or expanding source populations.
Dashed arrows show conversion events that occur infrequently due to small source populations.
(A) Without treatment, all resistant strains are less fit than the sensitive strain. Therefore, resistance emergence is not possible.
(B) Treatment of a small fraction of the population reduces fitness of the sensitive strain enough to allow for emergence of the fittest resistant strain. For that to happen, one frequent and two rare conversions need to occur.
(C) Further increase in treatment level allows both the second and third resistant strains to emerge. For the second resistant strain to emerge, one frequent and one rare conversion need to occur. Subsequently, the third resistant strain is rapidly generated and will outcompete all other strains.
(D) Treatment of a large fraction of the population results in all conversion events being frequent and in rapid emergence of resistance.