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      Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

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          Abstract

          Antimicrobial agents are currently the mainstay of treatment for bacterial infections worldwide. However, due to the increased use of antimicrobials in both human and animal medicine, pathogens have now evolved to possess high levels of multi-drug resistance, leading to the persistence and spread of difficult-to-treat infections. Several current antibacterial agents active against Gram-positive bacteria will be rendered useless in the face of increasing resistance rates. There are several emerging antibiotics under development, some of which have been shown to be more effective with an improved safety profile than current treatment regimens against Gram-positive bacteria. We will extensively discuss these antibiotics under clinical development (phase I-III clinical trials) to combat Gram-positive bacteria, such as Staphylococcus aureus, Enterococcus faecium and Streptococcus pneumoniae. We will delve into the mechanism of actions, microbiological spectrum, and, where available, the pharmacokinetics, safety profile, and efficacy of these drugs, aiming to provide a comprehensive review to the involved stakeholders.

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          Most cited references228

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          Antibiotics and Bacterial Resistance in the 21st Century

          Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.
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            Phage therapy: An alternative to antibiotics in the age of multi-drug resistance

            The practice of phage therapy, which uses bacterial viruses (phages) to treat bacterial infections, has been around for almost a century. The universal decline in the effectiveness of antibiotics has generated renewed interest in revisiting this practice. Conventionally, phage therapy relies on the use of naturally-occurring phages to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins. Current research on the use of phages and their lytic proteins, specifically against multidrug-resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments. Antibacterial therapies, whether phage- or antibiotic-based, each have relative advantages and disadvantages; accordingly, many considerations must be taken into account when designing novel therapeutic approaches for preventing and treating bacterial infections. Although much is still unknown about the interactions between phage, bacteria, and human host, the time to take phage therapy seriously seems to be rapidly approaching.
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              Type IIA topoisomerase inhibition by a new class of antibacterial agents.

              Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.
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                Author and article information

                Journal
                Microorganisms
                Microorganisms
                microorganisms
                Microorganisms
                MDPI
                2076-2607
                30 January 2020
                February 2020
                : 8
                : 2
                : 191
                Affiliations
                [1 ]UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia; elena.xu@ 123456uq.net.au (E.X.); a.song@ 123456uq.net.au (A.S.); isaac.mok1@ 123456uq.net.au (I.Y.S.M.); j.lipman@ 123456uq.edu.au (J.L.)
                [2 ]2nd Critical Care Department, Attikon University Hospital, 12462 Athens, Greece; aarmag@ 123456med.uoa.gr
                [3 ]4th Department of Internal Medicine, Attikon University Hospital, 12462 Athens, Greece; drkarag@ 123456gmail.com (D.E.K.); sotirios.tsiodras@ 123456gmail.com (S.T.)
                [4 ]Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia
                [5 ]Anesthesiology and Critical Care, Centre Hospitalier Universitaire De Nîmes (CHU), University of Montpellier, 30029 Nîmes, France
                Author notes
                [* ]Correspondence: d.koulenti@ 123456uq.edu.au
                [†]

                Equal contribution-both 3rd authors.

                [‡]

                They are joint senior authors.

                Author information
                https://orcid.org/0000-0003-4364-2612
                https://orcid.org/0000-0002-5999-966X
                https://orcid.org/0000-0001-5505-4215
                https://orcid.org/0000-0002-9959-9978
                https://orcid.org/0000-0002-0463-4321
                https://orcid.org/0000-0002-5965-9876
                Article
                microorganisms-08-00191
                10.3390/microorganisms8020191
                7074912
                32019171
                7000519b-df28-4df4-84c1-7de7ab8ad577
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 January 2020
                : 28 January 2020
                Categories
                Review

                emerging anti gram-positive antibiotics,multi-drug resistance organisms,clinical trials,dihydrofolate reductase inhibitors,ketolides,oxazolidinones,quinolones,defensin mimetics,β-lactams,topoisomerase ii inhibitors

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