Phagosomal acidification coordinates a lipid–redox program underlying antibiotic tolerance in Mycobacterium tuberculosis
Abstract
Abstract Phenotypically drug-tolerant Mycobacterium tuberculosis ( Mtb ) subpopulations within macrophages delay bacterial clearance, contributing to prolonged therapy and treatment failure. Here, we identify phagosomal acidification as a metabolic control point linking host lipid metabolism, bacterial redox homeostasis, and antibiotic tolerance. Acidic phagosomes promote lipid droplet (LD) biogenesis in macrophages, increasing lipid availability to intracellular Mtb . Access to host lipids enables Mtb to maintain a reductive cytoplasmic redox state that supports drug tolerance. Chloroquine (CQ)-mediated phagosomal alkalinization disrupted this pH–LD axis, reducing LD accumulation, bacterial lipid access, and redox-associated drug tolerance in both H37Rv and the multidrug-resistant clinical isolate NHN1664. Transcriptomic profiling of intraphagosomal Mtb identified the Fe–S cluster transcription factor WhiB6 as a candidate regulator linking phagosomal pH, host lipid availability, and reductive stress. In C3HeB/FeJ mice infected with NHN1664, CQ monotherapy attenuated lung fibrosis and improved pulmonary function without affecting bacterial burden. In this model, where necrotic and fibrotic lesions limit anti-tuberculosis drug efficacy, moxifloxacin (MXF) alone had little effect on bacterial burden, whereas CQ–MXF combination therapy significantly improved bacterial clearance. Collectively, these findings identify phagosomal acidification as a central regulator of…
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