Infections caused by the filamentous fungus Aspergillus fumigatus are a significant clinical
issue and represent the second most-common form of fungal infection. Azole drugs are
effective against this pathogen but resistant isolates are being found more frequently.
Infections associated with azole resistant A. fumigatus have a significantly increased
mortality making understanding drug resistance in this organism a priority. The target of
azole drugs is the lanosterol α-14 demethylase enzyme encoded by the cyp51A gene in A.
fumigatus. Mutations in cyp51A have been described that give rise to azole resistance and
been argued to be the primary, if not sole, contributor to azole resistance. Here, I discuss
recent developments that indicate multiple mechanisms, including increased expression
of ATP-binding cassette (ABC) transporter proteins, contribute to azole resistance. ABC
transporters arewell-established determinants of drug resistance in other fungal pathogens
and seem likely to play a similar role in A. fumigatus.