An Overview: Staphylococcus Aureus Phage Therapy
Total Page：16
File Type：pdf, Size：1020Kb
An overview: Staphylococcus aureus phage therapy Johan de Vries s3098168 Abstract Staphylococcus aureus (S. aureus) is a common and a frequent virulent pathogen in humans. S. aureus, a ubiquitous bacterium among humans, can cause severe infections such as cellulitis, sepsis and osteomyelitis. The emergence of antibiotics in the 1940s led to believe that bacterial infections would cease to exist. In 1959, however, bacteria started to gain resistance to antibiotics, including S. aureus. Despite the many attempts of developing new antibiotics, bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA) were unaffected. This has led to a renewed interest in phage therapy, a non-antibiotic approach to treat bacterial infections. Here, I will give an overview of the current state of S. aureus phage therapy. Introduction later from the United states were discovered. At the beginning of the 20th century, phage Methicillin-resistant Staphylococcus aureus therapy was being developed as a treatment (MRSA) is an important cause of hospital- against human and animal bacterial infections. acquired infections that are becoming more Bacteriophages, also known as phages, are difficult to treat because of the rising resistance viruses which specifically kill bacteria without to all antibiotics, and will be an even bigger interfering with cell lines from other organisms. cause of public health concern (Enright M.C. et This is because phages have a high specificity al., 2002). against certain cellular target hosts. This has led to a renewed interest in phage This form of treatment, however, was therapy, a non-antibiotic approach to treat overlooked in the Western World after the bacterial infections. Phages are the most emergence of antibiotics in the 1940s (Lin D.M. abundant microorganism on earth and are the et al., 2017; Chanishvili N., 2012; Wittebole X. natural regulators of bacterial populations. They et al., 2014). At that time, antibiotics were seen are able to induce bacterial lysis in Gram- as the ‘wonder drugs’ in the mid-20th century. negative as well as in Gram-positive bacteria, Prior to antibiotics, infectious diseases including MRSA (Sulakvelidze A., 2011; accounted for high mortality and morbidity rates Wittebole X. et al., 2014). worldwide. Infectious diseases such as In order to implement phage therapy against S. tuberculosis, syphilis, smallpox, cholera, aureus, S. aureus specific phages are needed. pneumonia etc. are nowhere near as high as Fortunately, Staphylococcal phages are seen today than they were before the use of plentiful, of which most are present as antibiotics. And thus with the emergence of prophages. Prophages are viral forms antibiotics, it was believed that these diseases integrated in bacterial genomes where they would cease to exist, and thereby improve the reside in their host until conditions favor their quality of life (Zaman S.B. et al., 2017; Adedeji reactivation, after which they activate the lytic W.A. et al., 2016). cyle (Fig. 4). Prophages contribute to the Yet in 1959 methicillin was introduced to treat virulence and pathogenesis of S. aureus by infections caused by penicillin-resistant S. encoding virulence factors. In order to aureus. After two years there were reports from implement phage therapy, phages which are the United Kingdom of S. aureus isolates that lytic (Fig. 4), specific to S. aureus and are had required resistance against methicillin. lacking pathogenic factors are suitable for S. Soon other methicillin-resistant S. aureus aureus phage therapy (Azam A.H. et al., 2019; isolates from other European countries, and Fortier L.C. et al., 2013). In this review, I will discuss the development As said earlier, all three of the Caudovirals and possible application of phage therapy families contain icosahedral capsids, which in against S. aureus. How come phage therapy turn contain a tightly packed linear double- may be a novel alternative to antibiotics, as well stranded DNA. The DNA, or rather the genome, as some of its downsides such as phage of the phages extends its size from 20 kb up to resistance. And in order to evaluate resistance 125 kb. The three classes of Caudovirals all of S. aureus to phages, it is of importance to get have a different sized genome, Myoviridae to know the mechanisms behind the attachment containing the largest one (>125 kb), of phages to S. aureus and elimination of S. podoviridae harboring the smallest genome aureus. (<20 kb) and Siphoviridae showing an in- between genome size (40 kb). Classification and morphology of S. Genomes of Siphoviridae show five functional aureus phages modules which are ordered as follows: In early studies by Rippon (1956), S. aureus lysogenic cycle, DNA metabolism, DNA phages have been classified on the basis of packaging and capsid formation, tail formation their lytic spectrum, serological group and host and lastly, host cell lysis. If virulence factors are range. This resulted in Eleven serological present, they generally are located downstream groups of phages indicated by the letters A – L of the lysis module. Although Podoviridae (Rees P.J. et al., 1980). All S. aureus infecting genomes show similar functional modules as phages belong to the Caudovirales. Siphoviridae¸ they do differ in the fact that some Caudovirales is an order of viruses also known modules are either not well defined or are as tailed bacteriophages. The tail is a special overlapping. Genome of Myoviridae are also organelle used for host recognition, cell wall organized into modules of conserved genes penetration and injection of the genome into the such as replication and structural elements, but host. Caudovirals are divided into three families: these modules are more likely to be interrupted Myoviridae, siphoviriae and podoviridae, which by regions encoding genes of unknown function is based on the tail morphology. Serological (Fig. 2) (Deghorian M. et al., 2012). group D belongs to the family Myoviridae, characterized by having an icosahedral capsid and the longest straight contractile tail out of the three families. Serological groups A, B and F are phages that belong to Podoviridae¸ which possess a short, blunt non-contractile tail and a small icosahedral capsid. Serological group G belongs to the Siphoviridae family and is characterized by having a small icosahedral capsid long flexible non-contractile tail (Fig. 1) (Fokine A. et al., 2014; Azam A. H. et al., 2019). Figure 2. organization of the functional modules of staphylococci phages genomes indicated by five colored boxes. Red: lysogeny, orange: DNA metabolism, green: DNA packaging and capsid morphogenesis, blue: tail morphogenesis, pink: cell host lysis, purple: virulence genes, grey: region encodes genes of unkown function. Note that only Siphoviridae possess virulence genes. Figure 1. Structure of Myoviridae phage (T4), (Deghorian M. et al., 2012). Podoviridae phage (φ29) and Siphiviridae phage (TP901-1) (Fokine A. et al., 2014). The tail of the phages is connected to the phage proteins seal the connector, preventing the capsids via a dodecameric portal, also known genome from exiting the capsid. The head as a connector. This connector allows the completion proteins also provide a binding site genome packaging to enter the prohead, or for the tail to bind to (Fokine A. et al., 2014). rather the capsid, during the virion assembly Since it may not have been clear what a phage and to exit during the infection process. life cycle looks like, an illustration (Fig. 4) has Figure 3. Internal scaffolding proteins help with the assembly of the phage capsid. This leads to the formation of the capsid precursor called prohead. The DNA packaging machine ensures that phage DNA enters the prohead. While the phage DNA is being packaged, the prohead undergoes structural rearrangement (head maturation), such as attachment of decoration prteins to their outer surface, to become the mature capsid. The head completion proteins assemble into a ring below the portal (connector), which allows the tail to connect to the connector. Now a mature virion (phage) has formed (Fokine A. et al., 2014). As illustrated in Fig. 3, scaffolding proteins help been added to this paragraph. The Podoviridae with the assembly of the phage capsids and and Myoviridae undergo a different life cycle ensure the correct geometry of the capsid. compared to Siphoviridae. Podoviridae and During the completion of the capsid, DNA Myoviridae both undergo a lytic cycle, while translocation motor package the phage genome Siphovidae undergo a lysogenic cycle. All three into the capsid. The DNA translocation motor is Caudovirales, however, attach to the bacterial driven by ATP hydrolysis. So as the DNA is host via a specific receptor on the surface of the being packaged, the capsid undergoes bacterium, after which they inject their genetic structural rearrangements and thus becomes a material into the cell. Lysogenic phages insert mature capsid. After the genome has been fully their genome into the host chromosome, this packed, the DNA translocation motor is prophage DNA gets replicated along with the removed from the capsid and head completion host chromosome. Only after certain signals, Figure 4. Lytic and Lysogenic phage life cycle. Lytic phages undergo the lytic cycle; after host recognition and adsorption, lytic phages inject their DNA into the host. After which the phage DNA is replicated, undergoes transcription and translation, which leads to synthesis of phage proteins and phage assembly. The last step of the lytic cycle is