WITHDRAWN: Reversing olorofim activity reveals multifactorial drug tolerance in Aspergillus fumigatus

Abstract

Drug tolerance leads to increased cell survival upon antimicrobial treatment and its contribution to the emergence of antimicrobial resistance is well described in bacteria. However, this antimicrobial response is still overlooked in human fungal pathogens, such as Aspergillus fumigatus. Due to the global increase of antifungal resistance to currently used antifungals to treat aspergillosis, new antifungals such as the pyrimidine synthesis inhibitor olorofim have been developed. Here, we show that reversing olorofim activity by the addition of exogenous pyrimidines reveals the presence of olorofim tolerance in 4% of A. fumigatus environmental isolates. Disrupting cell wall integrity or inhibiting efflux transport in those isolates reverses olorofim tolerance, yet inconsistently, thus suggesting that this response may have a multifactorial origin. Understanding the mechanistic basis of A. fumigatus tolerance to olorofim will increase our knowledge on its contribution to resistance allowing the development of strategies to suppress it before this promising antifungal reaches clinical implementation.