This study shows that a vitamin B6‑saving system in the bacteria that cause strep throat helps them survive attacks by our immune cells and the natural antibiotic peptide LL‑37. When the bacteria’s B6 pathway is broken, they die more easily in human blood, but the effect isn’t seen in mice. The findings mainly tell us how the bug evades our defenses, not how to use LL‑37 for health.

<i>Streptococcus pyogenes</i> (Group A <i>Streptococcus</i>, GAS) is a Gram-positive bacterium that inflicts both superficial and life-threatening diseases on its human host. Analysis of fitness using a transposon mutant library revealed that genes predicted to be involved in vitamin B₆ acquisition are associated with fitness in whole human blood. Vitamin B₆ is essential for all life and is important for many cellular functions. In several streptococcal species, it has been shown that mutants in B₆ acquisition exhibited reduced virulence phenotypes and were attenuated during infection. In GAS, B₆ acquisition is believed to be controlled by the <i>pdxR-pdxKU</i> locus, where PdxR is a positive regulator of <i>pdxKU</i>, which encodes for a B₆-substrate kinase and permease, respectively. Mutants in the regulator (&#x394;<i>pdxR</i>) and salvage machinery (&#x394;<i>pdxKU</i>) both exhibited modest growth defects when grown in oxygenated conditions with limited vitamin B₆ precursors. &#x2206;<i>pdxR</i> and &#x2206;<i>pdxKU</i> mutants also exhibited an impaired ability to survive when challenged with whole human or mouse blood. This defect was characterized by reduced survival in the presence of human neutrophil-like HL60s, primary polymorphonuclear leukocytes, and antimicrobial peptide LL-37. Promoter analysis showed that PdxR is an autoregulator and activated <i>pdxKU</i> in the absence of B₆. Interestingly, &#x2206;<i>pdxR</i> and &#x2206;<i>pdxKU</i> mutants were not attenuated in mouse models of infection, suggesting a species-specific impact on virulence. Overall, it appears that <i>pdxR-pdxKU</i> is associated with GAS vitamin B₆ metabolism as well as pathogen survival during encounters with the human innate immune system.IMPORTANCEBacterial pathogens such as <i>Streptococcus pyogenes</i> (Group A <i>Streptococcus</i>, GAS) must be able to obtain needed nutrients in their human host. Vitamin B₆ or pyridoxal 5' phosphate is essential for all life and is important for many cellular functions. In other streptococcal pathogens, B₆ acquisition has been shown to be important for their ability to cause disease. Here, we show that loss of the putative vitamin B₆ salvage pathway locus <i>pdxR-pdxKU</i> affects GAS pathogenesis when encountering innate immune responses from phagocytic neutrophils and antimicrobial peptides within the host. <i>pdxR-</i>pdxKU may contribute to oxygen tolerance through B₆; however, there appear to be other mechanisms for salvaging vitamin B₆. Overall, <i>pdxR-pdxKU</i> is associated with GAS resistance to the human innate immune response and oxygen tolerance and contributes modestly to B₆ metabolism.