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      Phage-Antibiotic Synergy Is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

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          Abstract

          Bacteriophage (phage) therapy is a promising approach to combat the rise of multidrug-resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

          ABSTRACT

          The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a few studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically based real-time microtiter plate readout with a matrix-like heat map of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of extraintestinal pathogenic Escherichia coli (ExPEC) with antibiotic levels blanketing the MIC across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug-resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, two different related phages that differed in their burst sizes produced drastically different synograms. Collectively, these data suggest lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria while also synergizing with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments.

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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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            Mechanism of Quinolone Action and Resistance

            Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone–enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains.
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              Antibiotic efficacy is linked to bacterial cellular respiration.

              Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes--the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                mBio
                mBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                4 August 2020
                Jul-Aug 2020
                : 11
                : 4
                : e01462-20
                Affiliations
                [a ]Tailored Antibacterials and Innovative Laboratories for Phage (Φ) Research (TAILΦR), Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
                [b ]School of Medicine, Baylor College of Medicine, Houston, Texas, USA
                [c ]Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
                [d ]Michael E. DeBakey Veterans Affairs Medical Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
                University of Texas Southwestern Medical Center Dallas
                Author notes
                Address correspondence to Anthony W. Maresso, Anthony.maresso@ 123456bcm.edu .
                Author information
                https://orcid.org/0000-0002-4491-3173
                Article
                mBio01462-20
                10.1128/mBio.01462-20
                7407087
                32753497
                30634757-0bc9-4512-9303-b276a1e8d21c
                Copyright © 2020 Gu Liu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 29 June 2020
                : 30 June 2020
                Page count
                supplementary-material: 6, Figures: 6, Tables: 0, Equations: 0, References: 59, Pages: 19, Words: 11206
                Funding
                Funded by: Mike Hogg Foundation;
                Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
                Funded by: U.S. Department of Veterans Affairs (VA), https://doi.org/10.13039/100000738;
                Award ID: VA I01-RX002595
                Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
                Funded by: Baylor College of Medicine (BCM), https://doi.org/10.13039/100007915;
                Award ID: Roderick D. MacDonald Research Fund
                Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
                Funded by: Baylor College of Medicine (BCM), https://doi.org/10.13039/100007915;
                Award ID: Seed Funds to TAILΦR
                Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient : Award Recipient :
                Categories
                Research Article
                Therapeutics and Prevention
                Custom metadata
                July/August 2020

                Life sciences
                synogram,synography,phage,antibiotic,adjuvant,synergy,phage therapy,escherichia coli,bacteriophage,clinical isolate,combinatorial treatment

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