Abstract
Author SummaryThe evolution of drug resistance in human pathogens is considered an inevitable consequence of the selective pressures imposed by antimicrobial drugs. Yet resistance to one antifungal drug, amphotericin B (AmB), remains extremely rare despite decades of widespread use. Here we explore the biological mechanisms underlying this conundrum. By examining natural and experimental populations of Candida albicans, we identify multiple mutations that confer resistance to AmB in vitro. As with the evolution of resistance to other antifungals, we find that the chaperone protein Hsp90 is involved in enabling the evolution of resistance to AmB. We also discover, however, that mutations that confer AmB resistance impose massive costs on other aspects of fungal pathogenicity; strains that are resistant to AmB are hypersensitive to attack by the host immune system and are unable to invade and damage host tissue. Thus, the evolution of resistance to AmB is restricted by a tradeoff between tolerance of the drug and the ability to cause disease. We propose that developing new antibiotics for which resistance presents such dire tradeoffs may be a promising strategy to prevent the evolution of resistance.
Highlights
Understanding how organisms rapidly evolve novel traits is a central problem in both evolutionary biology and the treatment of infectious diseases
The evolution of drug resistance in human pathogens is considered an inevitable consequence of the selective pressures imposed by antimicrobial drugs
By examining natural and experimental populations of Candida albicans, we identify multiple mutations that confer resistance to amphotericin B (AmB) in vitro
Summary
Understanding how organisms rapidly evolve novel traits is a central problem in both evolutionary biology and the treatment of infectious diseases. Sometimes resistance mechanisms are completely orthogonal to the normal biology of the cell, as is the case for the amplification of efflux pumps or the horizontal acquisition of drug-detoxifying enzymes in bacteria. Often the mutations that confer resistance alter basic cellular processes in such a way as to create a variety of new stresses. The latter is especially relevant in eukaryotic pathogens, where the rarity of genetic exchange within and between populations necessitates the de novo evolution of resistance [1,2]
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