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      Bacterial Metabolism and Antibiotic Efficacy

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          Summary

          Antibiotics target energy-consuming processes. As such, perturbations to bacterial metabolic homeostasis are significant consequences of treatment. Here, we describe three postulates that collectively define antibiotic efficacy in the context of bacterial metabolism: (1) antibiotics alter the metabolic state of bacteria, which contributes to the resulting death or stasis; (2) the metabolic state of bacteria influences their susceptibility to antibiotics; and (3) antibiotic efficacy can be enhanced by altering the metabolic state of bacteria. Altogether, we aim to emphasize the close relationship between bacterial metabolism and antibiotic efficacy as well as propose areas of exploration to develop novel antibiotics that optimally exploit bacterial metabolic networks.

          Abstract

          The metabolic state of bacteria significantly contributes to the efficacy of antibiotics. In this Perspective, Stokes et al. highlight the close relationship between bacterial cell metabolism and antibiotic efficacy, leveraging prior observations to describe areas for further exploration, with the goal of developing next-generation antibiotics that can optimally exploit the complex metabolic networks of bacteria.

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          Most cited references56

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          A common mechanism of cellular death induced by bactericidal antibiotics.

          Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
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            Physiological heterogeneity in biofilms.

            Biofilms contain bacterial cells that are in a wide range of physiological states. Within a biofilm population, cells with diverse genotypes and phenotypes that express distinct metabolic pathways, stress responses and other specific biological activities are juxtaposed. The mechanisms that contribute to this genetic and physiological heterogeneity include microscale chemical gradients, adaptation to local environmental conditions, stochastic gene expression and the genotypic variation that occurs through mutation and selection. Here, we discuss the processes that generate chemical gradients in biofilms, the genetic and physiological responses of the bacteria as they adapt to these gradients and the techniques that can be used to visualize and measure the microscale physiological heterogeneities of bacteria in biofilms.
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              Microbiota-mediated colonization resistance against intestinal pathogens.

              Commensal bacteria inhabit mucosal and epidermal surfaces in mice and humans, and have effects on metabolic and immune pathways in their hosts. Recent studies indicate that the commensal microbiota can be manipulated to prevent and even to cure infections that are caused by pathogenic bacteria, particularly pathogens that are broadly resistant to antibiotics, such as vancomycin-resistant Enterococcus faecium, Gram-negative Enterobacteriaceae and Clostridium difficile. In this Review, we discuss how immune- mediated colonization resistance against antibiotic-resistant intestinal pathogens is influenced by the composition of the commensal microbiota. We also review recent advances characterizing the ability of different commensal bacterial families, genera and species to restore colonization resistance to intestinal pathogens in antibiotic-treated hosts.
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                Author and article information

                Contributors
                Journal
                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                06 August 2019
                06 August 2019
                : 30
                : 2
                : 251-259
                Affiliations
                [1 ]Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                [2 ]Infectious Disease & Microbiome Program, Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA
                [3 ]Machine Learning for Pharmaceutical Discovery and Synthesis Consortium, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                [4 ]Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
                [5 ]Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland
                [6 ]Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA
                Author notes
                []Corresponding author jimjc@ 123456mit.edu
                Article
                S1550-4131(19)30312-2
                10.1016/j.cmet.2019.06.009
                6990394
                31279676
                ecd1a9e2-7243-4fe6-a1a8-2fd7f5ab66b2
                © 2020 The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Categories
                Article

                Cell biology
                bacterial metabolism,antibiotic mechanism,antibiotic tolerance,antibiotic adjuvants

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