Figure 2. Exploring the relationships between and mechanisms governing intrinsic and acquired resistance.

The development of acquired resistance can occur through several mechanisms. Examples include overexpression of the drug target, amino acid substitutions in the drug target that impede drug binding, signaling through stress response pathways, upregulation of efflux pumps, or alterations in cellular pathways. Acquired resistance in fungal pathogens can be accelerated via multiple factors including but not limited to an organisms’ genetic plasticity, the existence of hypermutator strains, or environmental pressures that result in strains becoming resistant to agricultural fungicides leading to cross resistance in clinical isolates. Primary resistance is achieved through several mechanisms overlapping with those implicated in acquired resistance including target incompatibility, stress response signaling, and efflux pump overexpression. In addition, the formation of fungal biofilms decreases overall fungal drug susceptibility, and differences in cellular permeability may prevent a drug from reaching its target. The combined effect of these contributing mechanisms leads the selection of increasingly resistant organisms.