How do bacteriophages transfer antibiotic resistance genes (ARGs)?

Antibiotics resistance genes transfer by bacteriophage
An illustration of ARG transfer by
T bacteriophages

Introduction

An effective prevention of infectious diseases is becoming a dream day after day due to the rise of antibiotics resistance. The drugs on the pipeline are no longer promising enough to end this worst case scenario in any time soon. The speed of bacteria becoming resistant to a new antibiotic is much higher in comparison with the drug development technology. While some bacterial strains display intrinsic resistance (example Aeromonas spp to ampicillin), others achieve antibiotic resistance by mutation, by the recombination of foreign DNA into the chromosome or by horizontal gene acquisition. In many cases, these three mechanisms operate together. Several mobile genetic elements (MGEs) have been reported to mobilize different types of resistance genes and despite sharing common features, they are often considered and studied separately. Bacteriophages and phage-related particles have recently been highlighted as MGEs that transfer antibiotic resistance.  Some studies suggested the use of bacteriophages in treating the bacterial infections through phage therapy. Bacteriophages have offered a promising alternative to AMR despite the fact that they also contribute to its raise.

Bacteriophages: viral shuttles carrying bacterial DNA

Bacteriophages, Like all viruses, phages are obligate intracellular parasites without intrinsic metabolism, which require the metabolic machinery of the host bacteria to support their reproduction. The complete structure of a phage commonly consists of a nucleic acid core (single or double‐stranded RNA or DNA but not both), an outer shell of protein capsid and in some cases a lipid envelope; many of them have additional structures as the tail, aimed to inject the nucleic acid through the cell wall). Bacteriophages are ultra‐microscopic (20–200 nm). Therefore, they shall be observed through transmission electron microscopy after capsid staining. In fact, the International Committee on Taxonomy of Viruses (ICTV) taxonomic system requires visualization of the phage particles by electron microscopy, among other characteristics, to determine capsid morphology to determine the phage taxonomy

Phages are recognized to be essential actors in different aspects of bacterial ecology, as for example bacterial population regulation, and more specifically gene, including ARGs, transfer. Metagenomic studies confirm that the majority of viruses in the viral fraction of most environments are bacteriophages, and that a large proportion of the viral particles contain bacterial DNA sequences, including linear chromosome fragments, and mobile elements such as insertion elements, transposons, plasmids and prophages. They influence the evolution of most bacterial species by promoting gene transfer. Moreover phage like particles have also evolved, which can package random pieces of host cell’s genome. The ubiquity and the great abundance of bacteriophages means that gene transfer from phages to bacteria occurs in a vast array of environments and ecosystems. The occurrence of phages harbouring ARGs has been reported in different matrices from human gut to ready to eat food. Since, bacteriophage‐mediated transfer of antibiotic resistance can occur in laboratories  transduction could be a significant contributor to emergence and persistence of antibiotic resistance in these environments affecting the food chain. In fact, transduction is acknowledged as a potential contributor to the spread of ARGs, especially between members of the same species . A capsid containing bacterial DNA is fully capable of binding to a recipient cell and injecting the foreign DNA. If the transferred bacterial DNA recombines into the genome of the recipient cell, or guaranties its autonomous replication (i.e. plasmids) transduction has occurred.

How do bacteriophages promote ARGs dissemination?

Phages bind to specific target receptors present on the bacterial cell surface, such that each phage generally targets a very narrow range of strains of the same bacterial species. Upon adsorption, phages inject their genomes into the bacterial cytoplasm and replicate by means of one or two main life cycles: the lytic cycle or the lysogenic (or temperate) cycle.

Antibiotics resistance genes transfer by bacteriophage
bacteriophage cycle

In the lytic cycle, the phage exploits the host cellular machinery, using it to replicate and manufacture new phage particles that are released following programmed cell lysis of an over‐burdened cell. In some cases, pseudo‐lysogeny can also occur, where the phage genome persists in non‐replicating cells until they return to replication and the bacteriophage follow its lytic cycle.

In the lysogenic cycle, the phage genome (termed a prophage) integrates into the bacterial genome, and replicates as part of the host chromosome, or as an independent replicon, in the absence of particle formation or cell lysis. Under specific circumstances, those of which induce the bacterial SOS response (antibiotic treatment, oxidative stress, irradiation or DNA damage), the prophage is induced and the lytic cycle is activated, and sometimes the phage genome incorporates host DNA from the genes located in the prophage integration locus , whereas those persisting as independent replicons incorporate random fragments.

During the lytic cycle released phages can randomly package and transfer bacterial DNA by a process called generalized transduction. Indeed, some mobile genetic elements have developed elegant and sophisticated strategies to hijack the phage DNA‐packaging machinery for their own transfer . Phage infection kills bacterial cells during the lytic cycle and small parts of bacterial DNA are occasionally captured in viral transducing particles. Therewith, bacterial population containing prophages can be considered as drivers of gene transfer in particular genes encoding antibiotic resistance. This context applies too to ARGs; thus, Haaber et al. (2016) demonstrated that release of phages from a population of S. aureus cells enables the intact prophage‐containing population to acquire ARGs from competing, phage‐susceptible strains present in the same environment. This fact would explain the rapid exchange of ARGs observed in S. aureus particularly and in other pathogenic bacteria. Although bacteriophages are generally thought to infect only a few strains of a given species, evidence in mounting that phages can have broader host ranges.

References

Dennis H Bamford, Jonathan M Grimes, David I Stuart,What does structure tell us about virus evolution?, Current Opinion in Structural Biology, Volume 15, Issue 6, 2005.
Lerminiaux NA, Cameron ADS. Horizontal transfer of antibiotic resistance genes in clinical environments. Can J Microbiol. 2019 Jan;65(1):34-44. doi: 10.1139/cjm-2018-0275. Epub 2018 Sep 24. PMID: 30248271.
Maiques E, Ubeda C, Campoy S, Salvador N, Lasa I, Novick RP, Barbé J, Penadés JR. beta-lactam antibiotics induce the SOS response and horizontal transfer of virulence factors in Staphylococcus aureus. J Bacteriol. 2006 Apr;188(7):2726-9. doi: 10.1128/JB.188.7.2726-2729.2006. PMID: 16547063; PMCID: PMC1428414.
Łoś M, Węgrzyn G. Pseudolysogeny. Adv Virus Res. 2012;82:339-49. doi: 10.1016/B978-0-12-394621-8.00019-4. PMID: 22420857. 
Bacteriophages as antibiotic resistance genes carriers in agro‐food systems 
S, . Jebri 
 
F. Rahmani 
 
F. Hmaied 
First published: 11 September 2020
Raphael Hans

Young scientist, phage enthusiast, and passionate about driving the development of bacteriophage therapy and application. Working as a research assistant at Makerere University.

Post a Comment

Previous Post Next Post