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      Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

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          Abstract

          Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.

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          Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa

          Benjamin Chan, Mark Sistrom, John Wertz … (2016)
          Increasing prevalence and severity of multi-drug-resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor-binding site. Results show that phage selection produces an evolutionary trade-off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections.
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            A century of the phage: past, present and future.

            George P. C. Salmond, Peter Fineran (2015)
            Viruses that infect bacteria (bacteriophages; also known as phages) were discovered 100 years ago. Since then, phage research has transformed fundamental and translational biosciences. For example, phages were crucial in establishing the central dogma of molecular biology - information is sequentially passed from DNA to RNA to proteins - and they have been shown to have major roles in ecosystems, and help drive bacterial evolution and virulence. Furthermore, phage research has provided many techniques and reagents that underpin modern biology - from sequencing and genome engineering to the recent discovery and exploitation of CRISPR-Cas phage resistance systems. In this Timeline, we discuss a century of phage research and its impact on basic and applied biology.
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              The global preclinical antibacterial pipeline

              Ursula Theuretzbacher, Kevin Outterson, Aleks Engel … (2019)
              Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of non-traditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work, focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antibiotics (Basel)
                Journal ID (iso-abbrev): Antibiotics (Basel)
                Journal ID (publisher-id): antibiotics
                Title: Antibiotics
                Publisher: MDPI
                ISSN (Electronic): 2079-6382
                Publication date (Electronic): 06 February 2020
                Publication date Collection: February 2020
                Volume: 9
                Issue: 2
                Electronic Location Identifier: 65
                Affiliations
                [1 ]Microbiology Department-Research Institute Biomedical A Coruña (INIBIC), Hospital A Coruña (CHUAC), University of A Coruña (UDC), 15009 A Coruña, Spain; olgapacios776@ 123456gmail.com (O.P.); luciablasco@ 123456gmail.com (L.B.); bleriot.ines@ 123456gmail.com (I.B.); laugemis@ 123456gmail.com (L.F.-G.); monica.gonzalez.bardanca@ 123456sergas.es (M.G.B.); anton17@ 123456mundo-r.com (A.A.); maria.lopez.diaz@ 123456sergas.es (M.L.); german.bou.arevalo@ 123456sergas.es (G.B.)
                [2 ]Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) of Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), 28003 Madrid, Spain
                [3 ]National Infection Service Laboratories, Public Health England, Colindale NW95EQ, UK
                [4 ]Spanish Network for the Research in Infectious Diseases (REIPI), 41071 Sevilla, Spain
                Author notes
                [* ]Correspondence: ma.del.mar.tomas.carmona@ 123456sergas.es ; Tel.: +34-981-176-399; Fax: +34-981-178-273
                Author information
                https://orcid.org/0000-0002-4476-856X
                https://orcid.org/0000-0002-4039-4142
                https://orcid.org/0000-0002-1846-4693
                https://orcid.org/0000-0002-8531-6105
                https://orcid.org/0000-0003-4501-0387
                Article
                Publisher ID: antibiotics-09-00065
                DOI: 10.3390/antibiotics9020065
                PMC ID: 7168131
                PubMed ID: 32041137
                SO-VID: 1b808c0a-93f8-4641-b2ae-8972e0f587f7
                Copyright © © 2020 by the authors.
                License:

                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
                Date received : 24 December 2019
                Date accepted : 01 February 2020
                Categories
                Subject: Review

                Keywords: anti-mdr strategies,anti-persistent treatments,drug repurposing
                Data availability:
                Keywords: anti-mdr strategies, anti-persistent treatments, drug repurposing

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