The L-lactate dehydrogenases of<i>Pseudomonas aeruginosa</i>are conditionally regulated but both contribute to survival during macrophage infection

Abstract Pseudomonas aeruginosais 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 is available to serve as a carbon source forP. aeruginosain the diverse settings it inhabits. Here, we evaluateP. aeruginosa’s production and use of its redundant L-lactate dehydrogenases, termed LldD and LldA. We confirm that the protein LldR represseslldDand identify a new transcription factor, called LldS, that activateslldA; these distinct regulators and the genomic contexts oflldDandlldAcontribute to their differential expression. We demonstrate that thelldDandlldAgenes are conditionally controlled in response to lactate isomers as well as to glycolate and ◻-hydroxybutyrate, which, like lactate, are ◻-hydroxycarboxylates. We also show thatlldAis induced when iron availability is low. Our examination oflldDandlldAexpression 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 revealed that bothlldDandlldAcontribute to persistence within host cells, underscoring the potential role of L-lactate as a carbon source duringP. aeruginosa-eukaryote interactions. Together, these findings help us understand the metabolism of a key resource that may promoteP. aeruginosa’s success as a resident of contaminated environments and animal hosts.Importance Pseudomonas aeruginosais a major cause of lung infections in people with cystic fibrosis, hospital-acquired infections, and 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 inP. aeruginosabiofilms. We uncovered mechanisms and identified compounds that controlP. aeruginosa’s LldD/LldA preference. 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 byP. aeruginosaand have the potential to inform the development of therapies targeting bacterial metabolism during infection..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 26. März Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:	Florek, Lindsey C. [VerfasserIn] Lin, Xi [VerfasserIn] Lin, Yu-Cheng [VerfasserIn] Lin, Min-Han [VerfasserIn] Chakraborty, Arijit [VerfasserIn] Price-Whelan, Alexa [VerfasserIn] Tong, Liang [VerfasserIn] Rahme, Laurence [VerfasserIn] Dietrich, Lars E.P. [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2024.03.21.586142

funding:
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PPN (Katalog-ID):	XBI04301044X