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Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill both Gram-positive and Gram-negative bacteria through simultaneous induction of oxidative, thiol and metal stress responses in bacteria. However, metabolic pathways through which PGRPs induce these bactericidal stress responses are unknown. We screened Keio collection of Escherichia coli deletion mutants and revealed that deleting genes for respiratory chain flavoproteins or for tricarboxylic acid (TCA) cycle resulted in increased resistance of E. coli to PGRP killing. PGRP-induced killing depended on the production of hydrogen peroxide, which required increased supply of NADH for respiratory chain oxidoreductases from central carbon catabolism (glycolysis and TCA cycle), and was controlled by cAMP-Crp. Bactericidal PGRP induced a rapid decrease in respiration, which suggested that the main source of increased production of hydrogen peroxide was a block in respiratory chain and diversion of electrons from NADH oxidoreductases to oxygen. CpxRA two-component system was a negative regulator of PGRP-induced oxidative stress. By contrast, PGRP-induced thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn2+ through influx of extracellular Zn2+ ) were mostly independent of oxidative stress. Thus, manipulating pathways that induce oxidative, thiol and metal stress in bacteria could be a useful strategy to design new approaches to antibacterial therapy.

We describe a case of platypnea-orthodeoxia syndrome in an 88-year-old man who presented with progressive dyspnea. Right-to-left shunting through a patent foramen ovale (PFO) was seen in the setting of normal right-sided heart pressures. He was successfully treated with percutaneous transcatheter PFO closure. (Level of Difficulty: Beginner.), Graphical abstract, This study describes a case of platypnea-orthodeoxia syndrome in an 88-year-old man who presented with progressive dyspnea. Right-to-left shunting…

Coronary artery disease is a leading cause of morbidity and mortality in the elderly, and with the aging population, it will remain an important healthcare concern. For patients with complex coronary artery disease, coronary artery bypass graft surgery (CABG) is often considered for

Right-to-left shunting across a PFO typically occurs with elevated right atrial pressures. Significant shunting can cause debilitating symptoms of hypoxia, leading to platypnea-orthodeoxia syndrome (POS). Here we describe a case of POS with PFO in the setting of normal right heart pressures. An 88

Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill both Gram-positive and Gram-negative bacteria through simultaneous induction of oxidative, thiol, and metal stress responses in bacteria. However, metabolic pathways through which PGRPs induce these bactericidal stress responses are unknown. We screened Keio collection of Escherichia coli deletion mutants and revealed that deleting genes for respiratory chain flavoproteins or for tricarboxylic acid (TCA) cycle resulted in increased resistance of E. coli to PGRP killing. PGRP-induced killing depended on the production of hydrogen peroxide, which required increased supply of NADH for respiratory chain oxidoreductases from central carbon catabolism (glycolysis and TCA cycle), and was controlled by cAMP-Crp. Bactericidal PGRP induced a rapid decrease in respiration, which suggested that the main source of increased production of hydrogen peroxide was a block in respiratory chain and diversion of electrons from NADH oxidoreductases to oxygen. CpxRA two-component system was a negative regulator of PGRP-induced oxidative stress. By contrast, PGRP-induced thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn2+ through influx of extracellular Zn2+) were mostly independent of oxidative stress. Thus, manipulating pathways that induce oxidative, thiol, and metal stress in bacteria could be a useful strategy to design new approaches to antibacterial therapy.