pharmaceuticals Review The Age of Phage: Friend or Foe in the New Dawn of Therapeutic and Biocontrol Applications? Ahmad Y. Hassan 1,2, Janet T. Lin 2, Nicole Ricker 3 and Hany Anany 1,4,* 1 Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON N1G 5C9, Canada; [email protected] 2 Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada; [email protected] 3 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada; [email protected] 4 Department of Food Science, Ontario Agricultural College, University of Guelph, Guelph, ON N1G 2W1, Canada * Correspondence: [email protected]; Tel.: +1-226-217-8067 Abstract: Extended overuse and misuse of antibiotics and other antibacterial agents has resulted in an antimicrobial resistance crisis. Bacteriophages, viruses that infect bacteria, have emerged as a legitimate alternative antibacterial agent with a wide scope of applications which continue to be discovered and refined. However, the potential of some bacteriophages to aid in the acquisition, maintenance, and dissemination of negatively associated bacterial genes, including resistance and virulence genes, through transduction is of concern and requires deeper understanding in order Citation: Hassan, A.Y.; Lin, J.T.; to be properly addressed. In particular, their ability to interact with mobile genetic elements such Ricker, N.; Anany, H. The Age of as plasmids, genomic islands, and integrative conjugative elements (ICEs) enables bacteriophages Phage: Friend or Foe in the New to contribute greatly to bacterial evolution. Nonetheless, bacteriophages have the potential to be Dawn of Therapeutic and Biocontrol used as therapeutic and biocontrol agents within medical, agricultural, and food processing settings, Applications?. Pharmaceuticals 2021, against bacteria in both planktonic and biofilm environments. Additionally, bacteriophages have 14, 199. https://doi.org/10.3390/ been deployed in developing rapid, sensitive, and specific biosensors for various bacterial targets. ph14030199 Intriguingly, their bioengineering capabilities show great promise in improving their adaptability and Academic Editor: Stephen T. Abedon effectiveness as biocontrol and detection tools. This review aims to provide a balanced perspective on bacteriophages by outlining advantages, challenges, and future steps needed in order to boost Received: 12 January 2021 their therapeutic and biocontrol potential, while also providing insight on their potential role in Accepted: 25 February 2021 contributing to bacterial evolution and survival. Published: 28 February 2021 Keywords: bacteriophage; phage therapy; biocontrol; transduction; antibiotic resistance Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction The use of antibiotics to treat a wide range of infections, saving millions of lives and revolutionizing the field of medicine since their discovery, has enabled them to be one of the most impactful scientific discoveries in modern history. However, the resulting Copyright: © 2021 by the Her Majesty consequences of their extensive use has signified a new era for medicine. The rapid the Queen in Right of Canada as rise of antibacterial resistance in bacteria across the globe, coupled with declines in the represented by the Minister of development of novel antibacterial agents, has resulted in the need for new approaches Agriculture and Agri-Food Canada; in combating bacterial infections [1]. Bacteriophages (phages), viruses that infect bacteria, Licensee MDPI, Basel, Switzerland. have emerged as a viable alternative to the declining utility of traditional antimicrobials to This article is an open access article mitigate the risk of pathogenic bacteria [2]. Their ubiquity in nature, versatility, and innate distributed under the terms and resiliency has elevated their status from mere research organisms to potentially viable and conditions of the Creative Commons necessary tools in the fight against rising antimicrobial resistance [3]. Attribution (CC BY) license (https:// While their potential utility and benefits continued to be examined and documented, creativecommons.org/licenses/by/ one of the key hurdles facing the progression and ultimate acceptance of bacteriophages for 4.0/). Pharmaceuticals 2021, 14, 199. https://doi.org/10.3390/ph14030199 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 37 While their potential utility and benefits continued to be examined and documented, one of the key hurdles facing the progression and ultimate acceptance of bacteriophages for therapeutic and biocontrol purposes is their ability to contribute to the horizontal Pharmaceuticalstransfer2021 of, 14genes,, 199 which can have negative consequences. The transfer of resistance, viru-2 of 35 lence, and other negatively associated genes via bacteriophages is a major area in which further examination and understanding is needed, so that proper steps may be taken to minimize its potentiallytherapeutic harmful and impacts. biocontrol purposes is their ability to contribute to the horizontal transfer Conversely, bacteriophagesof genes, which provide can have negativean incredible consequences. sense Theof versatility transfer of resistance, for potential virulence, and other negatively associated genes via bacteriophages is a major area in which further application. The use ofexamination whole phage and understanding particles and is needed, phage so components that proper steps continues may be taken to be to stud- minimize ied, as well as their itsuse potentially across a harmful variety impacts. of industries and purposes. The application of bacteriophages within medical,Conversely, agricultural, bacteriophages and provide food anprocessing incredible sensesettings of versatility provides for some potential of the most promisingapplication. opportunities The use for of their whole regulatory phage particles approval and phage and components commercialization continues to be studied, as well as their use across a variety of industries and purposes. The application of [4,5]. Their ability andbacteriophages potential efficacy within medical, to be used agricultural, against and bac foodteria processing in both settings planktonic provides and some of biofilm settings providethe most another promising reason opportunities for their for continued their regulatory examination approval and [ commercialization6]. Phages con- [4,5]. tinue to be studied asTheir not abilityonly andbacterial potential killers, efficacy but to be also used as against potential bacteria active in both bacterial planktonic anddetec- biofilm tors, and while understandingsettings provide surrounding another reason the form their remains continued relatively examination limited, [6]. Phages computa- continue to be studied as not only bacterial killers, but also as potential active bacterial detectors, tional and bioengineeringand while advancements understanding have surrounding the potential them remains to further relatively bolster limited, thecomputational utility of the bacterial viruses. and bioengineering advancements have the potential to further bolster the utility of the Therefore, we aimbacterial to provide viruses. a balanced perspective on bacteriophages in this review Therefore, we aim to provide a balanced perspective on bacteriophages in this review (Figure 1), outlining (Figurethe current1), outlining advantages, the current challenges advantages,, challenges,and future and steps future needed steps needed in order in order to boost their therapeuticto boost and their biocontrol therapeutic potential, and biocontrol while potential, also whileproviding also providing insight insight into intotheir their role in the acquisition,role maintenance, in the acquisition, and maintenance, dissemination and dissemination of genes that of genes may that benefit may benefit bacterial bacterial survival through transduction.survival through transduction. FigureFigure 1.1.Bacteriophages Bacteriophages and theand Antimicrobial the Antimicrobial Resistance Resistance Crisis: Friend Crisis: or Foe? Friend An overview or Foe? of variousAn overview phage-based of variousapplications phage and- examplesbased applications that display the and potential examples benefit andthat “friend” display aspect the ofpotential bacteriophages benefit (left and, green “friend” background aspectside) in of combatting bacteriophages antimicrobial (left resistant, green bacterial background strains, as side) well as in some combatting potentially detrimentalantimicrobial or negatively resistant associated bacte- rialoutcomes strains, that as can well contribute as some to thepotentially “foe” aspect detrimental of phage-based or usenegatively (right, red associated background outcomes side) and their that role can in the contributeacquisition, maintenance,to the “foe” and aspect dissemination of phage of- antibacterialbased use resistance(right, red genes. background side) and their role in the acquisition, maintenance, and dissemination of antibacterial resistance genes. 2. Bacterial Antimicrobial Resistance—An Ongoing Crisis 2.1. The Boom of Antibacterial Agents Pharmaceuticals 2021, 14, 199 3 of 35 2. Bacterial Antimicrobial Resistance—An Ongoing Crisis 2.1. The Boom of Antibacterial Agents Evidence exists showing the use of various substances for their