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Phage Therapy: an Alternative to Antibiotics in the Age of Multi-Drug Resistance

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Phage Therapy: an Alternative to Antibiotics in the Age of Multi-Drug Resistance Submit a Manuscript: http://www.f6publishing.com World J Gastrointest Pharmacol Ther 2017 August 6; 8(3): 162-173 DOI: 10.4292/wjgpt.v8.i3.162 ISSN 2150-5349 (online) REVIEW Phage therapy: An alternative to antibiotics in the age of multi-drug resistance Derek M Lin, Britt Koskella, Henry C Lin Derek M Lin, Henry C Lin, Section of Gastroenterology, New Abstract Mexico VA Health Care System, Albuquerque, NM 87108, United States The practice of phage therapy, which uses bacterial viruses (phages) to treat bacterial infections, has been Britt Koskella, Department of Integrative Biology, University of around for almost a century. The universal decline in California, Berkeley, Berkeley, CA 94720, United States the effectiveness of antibiotics has generated renewed interest in revisiting this practice. Conventionally, phage Henry C Lin, Department of Medicine, University of New therapy relies on the use of naturally-occurring phages Mexico, Albuquerque, NM 87131, United States to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the Author contributions: All authors contributed equally to this repertoire of potential phage therapeutics to include novel work with regard to the scope of the subject, the literature review strategies using bioengineered phages and purified phage and analysis, drafting, revision, editing, and final approval of the lytic proteins. Current research on the use of phages manuscript. and their lytic proteins, specifically against multidrug- Supported by Winkler Bacterial Overgrowth Research Fund (in resistant bacterial infections, suggests phage therapy part). has the potential to be used as either an alternative or a supplement to antibiotic treatments. Antibacterial Conflict-of-interest statement:No potential conflicts of interest. therapies, whether phage- or antibiotic-based, each have relative advantages and disadvantages; accordingly, Open-Access: This article is an open-access article which was many considerations must be taken into account when selected by an in-house editor and fully peer-reviewed by external designing novel therapeutic approaches for preventing reviewers. It is distributed in accordance with the Creative and treating bacterial infections. Although much is still Commons Attribution Non Commercial (CC BY-NC 4.0) license, unknown about the interactions between phage, bacteria, which permits others to distribute, remix, adapt, build upon this and human host, the time to take phage therapy seriously work non-commercially, and license their derivative works on seems to be rapidly approaching. different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ Bacteriophage; Bacteriophage therapy; Phage; licenses/by-nc/4.0/ Key words: Phage therapy; Endolysin; Lysin; Multidrug resistance; Manuscript source: Invited manuscript Antibiotic resistance; Phage safety; Methicillin-resistant Staphylococcus aureus Correspondence to: Henry C Lin, MD, Section of Gastro- enterology, New Mexico VA Health Care System, 1501 San © The Author(s) 2017. Published by Baishideng Publishing Pedro SE, Albuquerque, NM 87108, Group Inc. All rights reserved. United States. [email protected] Telephone: +1-505-2561711-4552 Core tip: Phage therapy is widely being reconsidered as an alternative to antibiotics. The use of naturally-occurring Received: November 2, 2016 phages to treat bacterial infection has a contentious Peer-review started: November 4, 2016 First decision: December 15, 2016 history in western medicine. However, the emergent Revised: May 13, 2017 landscape of phage-based antimicrobials has advanced Accepted: May 30, 2017 well beyond traditional methods. In this rapidly evolving Article in press: May 31, 2017 field, novel technologies such as bioengineered chimeras Published online: August 6, 2017 of phage-derived lytic proteins show potential as a new WJGPT|www.wjgnet.com 162 August 6, 2017|Volume 8|Issue 3| Lin DM et al . Assessing phage antimicrobials for antibiotic-resistant infections class of antibacterial pharmaceuticals. This review aims to of common diseases, and these genes now appear provide a topical perspective on the historical context of to be abundant in the environment[8]. The spread of phage therapy, in order to highlight modern advances in antibiotic resistance genes carries a unique danger in phage research and innovations in the field. that many antibiotics have diminishing efficacy against common infections, particularly the difficult-to-treat nosocomial infections caused by the ESKAPE pathogens Lin DM, Koskella B, Lin HC. Phage therapy: An alternative (Enterococcus faecium, Staphylococcus aureus, Kle­ to antibiotics in the age of multi-drug resistance. World J bsiella pneumoniae, Acinetobacter baumannii, Pseu­ Gastrointest Pharmacol Ther 2017; 8(3): 162-173 Available domonas aeruginosa, and Enterobacter spp.). from: URL: http://www.wjgnet.com/2150-5349/full/v8/i3/162. Admonitions of a return to “the pre-antibiotic era” htm DOI: http://dx.doi.org/10.4292/wjgpt.v8.i3.162 have become increasingly common and regulatory organizations such as the Centers for Disease Control (CDC) and WHO have declared antibiotic resistance a threat to global health[9,10]. The CDC estimates anti- INTRODUCTION biotic-resistant infections result in 2 million illnesses and at least 23000 deaths a year, with many more Almost a decade before the discovery of penicillin, dying from conditions complicated by antibioticre- the controversial practice of phage therapy was being sistant infections, costing the United States $55 developed as a treatment for bacterial infections. billion annually[7]. According to the United Kingdom Phages, short for bacteriophages, are bacteria-specific government’s 2016 Review on Antimicrobial Resistance, viruses that have been used as a treatment against an estimated 700000 people die each year globally pathogens such as Shigella dysenteriae as early as from resistant infections with a projected cost of $100 [1] 31 32 1919 . With an estimated 10 -10 phages in the trillion and a death toll of 10 million by 2050[7]. In the [2] world at any given time , they make up the most United States, methicillin-resistant S. aureus (MRSA) abundant biological entity on Earth and play a crucial infections alone account for more deaths than HIV/AIDS role in regulating bacterial populations; phages are and tuberculosis combined[11]. Since the discovery of responsible for the death of approximately 20%-40% antibiotics, there has been a steady stream of novel [3] of all marine surface bacteria every 24 h . Much of antibacterial pharmaceuticals in what has been dubbed the controversy surrounding phage therapy was due to the “antibiotic pipeline”. However, due to the rate at poor documentation of use and variable success. The which bacteria evolve resistance to antibiotics, there complications in implementing phage therapy stemmed has been less commercial interest in the research from how little was known about phages at the time and development of novel compounds. In the years of their discovery. In fact, the nature of their existence of 1983-1987, there were 16 new pharmaceutical was a topic of contention until they were visualized in antibiotics approved by the Food and Drug Admini- [4] the 1940’s after the invention of electron microscopy . stration (FDA) for use in the United States, this num- A number of logistical and technical obstacles in ber has steadily trended downwards and between developing phage therapy led to its widespread 2010-2016 only 6 new antibiotics were approved[12]. At abandonment after the discovery of antibiotics. the end of the antibiotic pipeline is the carbapenem class The advent of pharmaceutical antibiotics in the of antibiotics, often reserved as the “last resort” due to th mid-20 century, along with a better understanding their adverse effects on health. Beginning in 2000, the of disease and sanitation, revolutionized healthcare incidence of carbapenem-resistant, hospital-acquired K. and drastically improved both quality of life and life pneumoniae infections began to increase in the United expectancy in the industrialized world. In 1900, life States; due to the lack of treatment options, these expectancy for men and women in the United States infections are associated with a 40%-50% mortality was 46 and 48, respectively, and the major causes of rate[13]. Reaching the end of the antibiotic pipeline could death were infectious diseases, many of which were signal a shift in the global culture of infectious disease bacterial (e.g., cholera, diphtheria, typhoid fever, treatment and some claim is the imminent return to a plague, tuberculosis, typhus, scarlet fever, pertussis, pre-antibiotic era of medicine. and syphilis)[5]. Antibiotics helped usher in a new era in On September 21, 2016, the United Nations General medicine, rapidly becoming an indispensable medical Assembly convened to discuss the problem of antibiotic tool with 262.5 million treatment courses prescribed resistance and deemed it “the greatest and most urgent in the United States in 2011 alone (842 prescriptions global risk”[14]. In the hunt for alternative strategies per 1000 persons) and an estimated 100000-200000 for prophylaxis and control of bacterial infection, one tons of antibiotics used globally between medicine, of the more popular suggestions involves revisiting agriculture, and horticulture each year[6,7]. Antibiotic the practice of phage therapy. Proponents of phage resistance genes
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