Acetate modulates host physiology and bacterial energetics to improve antibiotic efficacy during obesity-associated infection

ABSTRACT Antibiotic efficacy is conventionally attributed to the susceptibility of the infecting pathogen. However, obese patients experience disproportionately poor infection outcomes despite receiving antibiotics to which pathogens remain genetically susceptible. These observations suggest that host-associated factors can influence treatment outcomes independently of the bacterial genotype, although the underlying mechanisms remain poorly understood. Using a mechanistic comparison of diet-induced obese and healthy mice infected with Acinetobacter baumannii , we demonstrate that the effect of antibiotics is not solely a property of the pathogen but can be governed by a gut microbiota-derived metabolite acting on both host immunity and bacterial physiology. We identify obesity-associated acetate depletion as a key driver of antibiotic treatment failure, linking gut microbial metabolism to antibiotic activity during infection. We observed that this depletion impaired innate immune activation, reducing cytokine responses and neutrophil-mediated bacterial clearance. Under these conditions, A. baumannii displayed enhanced tolerance to bactericidal antibiotics, particularly tobramycin. Given these findings, we investigated whether acetate could be leveraged therapeutically to restore antibiotic efficacy. We observed that oral acetate supplementation remodeled the dysbiotic microbiome, whereas systemic acetate restored innate immune competence and neutrophil-mediated bacterial clearance. Most importantly, acetate reversed antibiotic tolerance and restored aminoglycoside killing by directly sensitizing host-induced tolerant bacterial populations. Mechanistically, acetate directly reprogrammed bacterial physiology to enhance aminoglycoside-mediated killing. Combined acetate-tobramycin treatment resulted in eradication of tolerant populations and markedly improved bacterial clearance in vivo . Our findings establish a mechanistic link between host metabolic state and antibiotic efficacy and identify acetate as a therapeutic intervention for obesity-associated gram-negative infections. IMPORTANCE Antibiotic treatment failure in obese patients remains poorly understood and therapeutically unaddressed. This study reveals that host metabolic state can control antibiotic response through a gut microbiota-derived metabolite that acts on both host defense and bacterial physiology. We identify obesity-driven depletion of microbiota-derived acetate as a previously unrecognized determinant of antibiotic failure, operating independently of bacterial resistance. By simultaneously restoring gut microbial balance, rescuing impaired innate immunity, and directly sensitizing pathogens to aminoglycoside killing through bacterial membrane alteration, acetate supplementation addresses the host-pathogen-microbiome axis through a single intervention. Given its established clinical safety, acetate represents a compelling combination therapy alongside aminoglycosides in obesity-associated gram-negative infections in a population for which host-directed treatment strategies are currently limited.