The L-lactate Dehydrogenases of Are Conditionally Regulated but Both Contribute to Survival During Macrophage Infection

is an opportunistic pathogen that thrives in environments associated with human activity, including soil and water altered by agriculture or pollution. Because L-lactate is a significant product of plant and animal metabolism, it can serve as a carbon source for in the diverse settings that it inhabits. In this study, we evaluate the production and use of two redundant L-lactate dehydrogenases, termed LldD and LldA. We confirm that the protein LldR represses and identify a new transcription factor, called LldS, that activates ; these distinct regulators and the genomic contexts of and contribute to their differential expression. We demonstrate that the and genes are conditionally controlled in response to lactate isomers as well as to glycolate and ɑ-hydroxybutyrate, which, like lactate, are ɑ-hydroxycarboxylates. We also show that is induced when iron availability is low. Our examination of and expression across depth in biofilms indicates a complex pattern that is consistent with the effects of glycolate production, iron availability, and cross-regulation on enzyme preference. Finally, macrophage infection assays reveal that both and contribute to persistence within host cells, underscoring the potential role of L-lactate as a carbon source during eukaryote interactions. Together, these findings help us understand the metabolism of a key resource that may promote 's success as a resident of contaminated environments and animal hosts.IMPORTANCE is a major cause of lung infections in people with cystic fibrosis, of hospital-acquired infections, and of wound infections. It consumes L-lactate, which is found at substantial levels in human blood and tissues. In this study, we investigated the spatial regulation of two redundant enzymes, called LldD and LldA, which enable L-lactate metabolism in biofilms. We uncovered mechanisms and identified compounds that control the preference of for LldD versus LldA. We also showed that both enzymes contribute to its ability to survive within macrophages, a behavior that is thought to augment the chronicity and recalcitrance of infections. Our findings shed light on a key metabolic strategy used by and have the potential to inform the development of therapies targeting bacterial metabolism during infection.