title: A central role for carbon-overflow pathways in the modulation of bacterial cell death.
abstract: Similar to developmental programs in eukaryotes, the death of a subpopulation of cells is thought to benefit bacterial biofilm development. However mechanisms that mediate a tight control over cell death are not clearly understood at the population level. Here we reveal that CidR dependent pyruvate oxidase (CidC) and α-acetolactate synthase/decarboxylase (AlsSD) overflow metabolic pathways, which are active during staphylococcal biofilm development, modulate cell death to achieve optimal biofilm biomass. Whereas acetate derived from CidC activity potentiates cell death in cells by a mechanism dependent on intracellular acidification and respiratory inhibition, AlsSD activity effectively counters CidC action by diverting carbon flux towards neutral rather than acidic byproducts and consuming intracellular protons in the process. Furthermore, the physiological features that accompany metabolic activation of cell death bears remarkable similarities to hallmarks of eukaryotic programmed cell death, including the generation of reactive oxygen species and DNA damage. Finally, we demonstrate that the metabolic modulation of cell death not only affects biofilm development but also biofilm-dependent disease outcomes. Given the ubiquity of such carbon overflow pathways in diverse bacterial species, we propose that the metabolic control of cell death may be a fundamental feature of prokaryotic development.
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Vinai Chittezham
authors.initials: VC
authors.lastname: Thomas
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Marat R
authors.initials: MR
authors.lastname: Sadykov
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Sujata S
authors.initials: SS
authors.lastname: Chaudhari
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Joselyn
authors.initials: J
authors.lastname: Jones
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Endres
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Widhelm
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Jong-Sam
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Department of Surgery, Stony Brook University School of Medicine, Stony Brook, New York, United States of America.
authors.forename: Randeep S
authors.initials: RS
authors.lastname: Jawa
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
authors.affiliation: Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bayles
mesh_terms: D000085:Acetates / Q000378:metabolism; D000095:Acetolactate Synthase / Q000378:metabolism*; D000818:Animals; D018441:Biofilms / Q000254:growth & development*; D002244:Carbon / Q000378:metabolism; D002262:Carboxy-Lyases / Q000378:metabolism*; D004249:DNA Damage; D004697:Endocarditis, Bacterial / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015964:Gene Expression Regulation, Bacterial; D010101:Oxygen Consumption; D011771:Pyruvate Oxidase / Q000378:metabolism*; D011817:Rabbits; D017382:Reactive Oxygen Species; D013211:Staphylococcus aureus / Q000378:metabolism*
chemical_list: D000085:Acetates; D017382:Reactive Oxygen Species; D002244:Carbon; D011771:Pyruvate Oxidase; D000095:Acetolactate Synthase; D002262:Carboxy-Lyases; C023746:acetolactate decarboxylase