In Bacillus subtilis, iron homeostasis is maintained by the ferric uptake regulator (Fur) and manganese homeostasis relies on the manganese transport regulator (MntR). Both Fur and MntR function as bi-functional metalloregulators that repress import and activate metal ion efflux systems. The ferrous iron efflux ATPase, PfeT, is derepressed by hydrogen peroxide (H₂O₂) as sensed by PerR and induced by iron as sensed by Fur. Mutants lacking PfeT are sensitive to iron intoxication. Here, we show that mntR mutants are also iron-sensitive, largely due to decreased expression of the MntR-activated MneP and MneS cation diffusion facilitator (CDF) proteins previously defined for their role in Mn²⁺ export. The ability of MneP and MneS to export iron is apparent even when their expression is not induced by Mn²⁺. Our results demonstrate that PfeT, MneP and MneS each contribute to iron homeostasis, and a triple mutant lacking all three is more iron-sensitive than any single mutant. We further show that sensitivity to H₂O₂ does not correlate with iron sensitivity. For example, an mntR mutant is H₂O₂-sensitive due to elevated Mn(II) that increases PerR-mediated repression of peroxide resistance genes, and this repression is antagonized by elevated Fe²⁺ in an mntR pfeT mutant. Thus, H₂O₂-sensitivity reflects the relative levels of Mn²⁺ and Fe²⁺ as sensed by the PerR regulatory protein. These results underscore the complex interplay between manganese, iron and oxidative stress in B. subtilis.

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