Widespread fungal–bacterial competition for magnesium lowers bacterial susceptibility to polymyxin antibiotics

by Yu-Ying Phoebe Hsieh, Wanting Sun, Janet M. Young, Robin Cheung, Deborah A. Hogan, Ajai A. Dandekar, Harmit S. Malik

Fungi and bacteria coexist in many polymicrobial communities, yet the molecular basis of their interactions remains poorly understood. Here, we show that the fungus Candida albicans sequesters essential magnesium ions from the bacterium Pseudomonas aeruginosa. To counteract fungal Mg²⁺ sequestration, P. aeruginosa expresses the Mg²⁺ transporter MgtA when Mg²⁺ levels are low. Thus, loss of MgtA specifically impairs P. aeruginosa in co-culture with C. albicans, but fitness can be restored by supplementing Mg²⁺. Using a panel of fungi and bacteria, we show that Mg²⁺ sequestration is a general mechanism of fungal antagonism against gram-negative bacteria. Mg²⁺ limitation enhances bacterial resistance to polymyxin antibiotics like colistin, which target gram-negative bacterial membranes. Indeed, experimental evolution reveals that P. aeruginosa evolves C. albicans-dependent colistin resistance via non-canonical means; antifungal treatment renders resistant bacteria colistin-sensitive. Our work suggests that fungal–bacterial competition could profoundly impact polymicrobial infection treatment with antibiotics of last resort.