Identifying and targeting the Mg-Fe-PmrAB regulatory circuit reverses phosphate starvation-driven polymyxin tolerance in Enterobacteriaceae

Phosphate limitation induces polymyxin tolerance in Enterobacteriaceae by triggering lipid A L-Ara4N modification, driven by arn operon induction via the PmrAB two-component system.

• Why it matters: Pi scarcity is common in infections and dysbiotic host environments, but Enterobacteriaceae lack the membrane phospholipid remodeling pathways seen in other bacteria, leaving their tolerance mechanism unclear.
• What they did: The study shows Pi limitation robustly increases L-Ara4N-modified lipid A through arn induction mediated by PmrAB, and links this to Mg2+ release followed by Fe3+ mobilization that activates PmrAB.
• The result: Mg2+ supplementation or Fe3+ chelation suppresses PmrAB activation and restores polymyxin susceptibility, enabling a metal-dependent strategy to reverse Pi starvation-driven tolerance in Enterobacteriaceae.

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