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Abstract The global rise of antimicrobial resistance poses a serious threat to public health. Because drug-resistant (DR) pathogens typically carry mutations in genes involved in critical cellular functions, they may be less fit under drug-free conditions than their susceptible counterparts. As such, the limited use of antimicrobial drugs has been proposed as a practical strategy to diminish the prevalence of DR strains. However, in many cases the fitness of DR pathogens under host conditions is unknown. Candida (Nakaseomyces) glabrata is a prevalent opportunistic fungal pathogen notable for its high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida pathogens. Nonetheless, the fitness of C. glabrata MDR isolates is poorly characterized, and studies of FLZR isolate fitness have produced contradictory findings. Two important host niches for C. glabrata are macrophages, in which it can survive and proliferate, and the gut. Herein, by employing a comprehensive collection of clinical and isogenic C. glabrata isolates, we show that FLZR C. glabrata isolates are less fit inside macrophages than susceptible isolates and that this fitness cost is reversed by acquiring ECR mutations in FKS1/2 genes. Interestingly, dual-RNAseq revealed that macrophages infected with DR isolates mount an inflammatory response whereas the intracellular DR cells downregulate processes required for in-host adaptation. Consistently, DR isolates were outcompeted by their susceptible counterparts in the context of gut colonization and the kidney of systemically infected mice, whereas they showed comparable fitness in the spleen. Collectively, our study shows that macrophage-rich organs, such as the spleen, favor the retention of DR isolates, potentially reducing the utility of limited antifungal use to decrease the burden of DR C. glabrata in the context of candidemia.
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