Many pathogens evade immune defence by residing within macrophages, cells that also drive pathological inflammation during infections. Approaches that amplify antimicrobial responses and suppress inflammatory responses in macrophages may thus have potential as immune-directed anti-infectives to combat antimicrobial resistance (AMR). Engagement of the pentose phosphate pathway (PPP) in macrophages fuels NADPH production that is required for antimicrobial reactive oxygen species (ROS) production and bacterial killing. PPP activation also selectively suppresses inflammatory cytokine production via the the PPP enzyme 6-phosphogluconate dehydrogenase (6PGD) product, ribulose-5-phosphate (RL5P). Here I explored the use of mRNA therapeutics and small molecule metabolites to enhance the PPP as an anti-infective and anti-inflammatory approach. Delivery of an mRNA encoding 6PGD to primary mouse macrophages suppressed lipopolysaccharide (LPS)-induced production of specific inflammatory mediators (e.g. IL-1B, IL-12p40), while nanoparticle-mediated administration of this mRNA in a mouse LPS shock model reduced similar inflammatory mediators in tissues. In humans, 6PGD mRNA expression in the liver also strongly inversely correlates with levels of the clinical inflammation marker C-reactive protein. Similarly, the enzymatic product of 6PGD, RL5P, attenuated specific inflammatory responses in primary human and mouse macrophages, whereas this effect was not observed with the upstream metabolite 6-phosphogluconate (6PG). Treatment of macrophages with RL5P, or combined delivery of mRNAs encoding the NADPH-generating PPP enzymes 6PGD and glucose-6-phosphate dehydrogenase (G6PD) also promoted bacterial killing by macrophages in vitro. Anti-inflammatory and antibacterial mechanisms of the 6PGD-RL5P axis were then investigated through transcriptomics and metabolomics. 6PGD target genes were enriched for the oxidative stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Accordingly, RL5P triggered ROS-dependent NRF2 protein expression in macrophages, with this being required for RL5P-inducible expression of antimicrobial and antioxidant genes. In contrast, RL5P suppressed inflammatory mediators independently of NRF2. Amplifying the 6PGD-RL5P axis may have applications in anti-inflammatory and/or anti-infective design.