Toxin-Antitoxin Systems in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an absolute aerobic gram-negative bacterium that has attracted the attention of many researchers for many years. There are plenty of reasons to research on P. aeruginosa , which unfortunately has made it an invincible bacterium. Adaptation to environmental changes is one of the most important capabilities that organisms need to survive. This rule also applies to the world of bacteria. P. aeruginosa is one of the most well-known bacteria in terms of adaptation to a variety of biological environments. Besides, P. aeruginosa has a variety of hosts, including humans. It is known as an opportunistic pathogen, therefore infections caused by P. aeruginosa are highly important in immunocompromised patients and it is a major cause of mortality and morbidity in cystic fibrosis patients. Also, P. aeruginosa is the most important cause of nosocomial infections, which can seriously threaten the lives of hospitalized patients. Severe resistance to most antibiotics is one of the other reasons for its success in causing infection and survival. P. aeruginosa can produce many powerful virulent factors that create unique properties in this bacterium. In this chapter, the general characteristics of P. aeruginosa are briefly and usefully explained. So, the reader can get a good idea of this bacterium in a short glance.

The greenish-blue color dye on the wounds and bandages of patients was the first characteristic that attracted the attention of researchers in the discovery of this bacterium. Eventually, in 1882, a French pharmacist, Carle Gessard discovered P. aeruginosa from colored cutaneous wounds. He also suggested that this bacterium may be associated with many diseases. Over time, this bacterium found its special niche in the biological and medical sciences due to the complexity, the production of various extracellular products, and the lack of information on how exactly the disease is caused. Along with these findings, several names were assigned to this bacillus bacterium. Finally,Pseudomonas aeruginosa was assigned based on the meaning and concept of title root and appearance of the bacterium. In a general sense, Pseudomonas aeruginosa was referred to the identical units of cells that produced a significant amount of greenish-blue color.

P. aeruginosa can cause a variety of infections in different hosts. For this purpose, it regulates several virulence factors depending on the surrounding conditions and environments. As a result, the type and severity of diseases vary from host to host. For instance, it causes acute infection in some patients, while it causes chronic infections in others. On the other hand, it can sometimes be very deadly and sometimes easy to treat. The difference in the behavior of P. aeruginosa is directly related to the expression of key virulence factors. In this chapter, major virulence factors and their roles in pathogenicity that are related to human diseases are comprehensively discussed. These virulence factors including, lipopolysaccharide, adhesions, lectins, alginate, flagella, pigments, biofilm, toxins, enzymes, proteases, etc. It should be noted that recognition and familiarity with virulence factors can be very helpful and effective to understand P. aeruginosa pathogenesis. Therefore, we discussed the structure as well as the manner of virulence factors intervention in P. aeruginosa infections. We hope to create a general idea of P. aeruginosa structure in the minds of the readers at the end of this chapter.

One of the most important features of P. aeruginosa is its ability to inhabit anywhere, especially in humid environments, which is very important in its dissemination. So, hygiene in public places such as swimming pools or hot tubs can be effective in reducing the incidence of this bacterium. On the other hand, P. aeruginosa is one of the main factors of nosocomial infections. Meanwhile, hospitalized patients in intensive care units are at greater risk. Fortunately, P. aeruginosa is sensitive to drought, so it is rarely transmitted through surfaces. In contrast, it can be spread through water-related devices such as respiratory therapy equipment, catheters, dialysis tubes, etc. P. aeruginosa is responsible for 11-13.8% of nosocomial infections including, urinary tract infection, pneumonia, burn wound infection and a blood infection, surgical site infection, etc. It is also important in patients with immunedeficiency like those who suffer from cystic fibrosis, severe leukemia, and AIDS. Since P. aeruginosa is ubiquitous and opportunistic bacterium, studying its epidemiology can be very effective and helpful in controlling diseases.

The importance of understanding the pathogenesis of infectious agents is in the diagnosis of the diseases and finding new treatments. In the case of P. aeruginosa pathogenesis, the issue is extremely broad and complex. Also, many aspects of its pathogenesis remain unknown to researchers. At a glance, P. aeruginosa causes acute and chronic infections. In addition, P. aeruginosa is an opportunistic bacterium that is highly dangerous in immunocompromised patients. In some cases, it can also threaten human life and causes the death of the patients. The ability of P. aeruginosa to cross the body barriers is so fascinating, which can penetrate the skin and even depths of the bone and joints. Although the pathogenesis of P. aeruginosa depends on many factors, it is attributed to several diseases including, bacteremia, keratitis, pneumonia, bone and joints infection, respiratory tract infection, urinary tract infection, skin and soft tissue infection, ear infection, endocarditis, central nervous system infection, enteric infection, mastitis and, etc. The wide range of diseases caused by P. aeruginosa clearly demonstrated the importance of this bacterium in the fields of medicine.

Due to the high potency of P. aeruginosa in pathogenesis and diffusion in the human body, it can be diagnosed in a variety of clinical specimens. For this purpose, the unique properties of P. aeruginosa are used. In general, the appearance of the bacterium under the microscope and its features on culture media as well as biochemical tests are widely used for the initial diagnosis of P. aeruginosa in the clinical laboratories. In this section, the diagnostic routine tests are briefly discussed so the readers can easily use them.

P. aeruginosa belongs to the group of the pathogens that is in dire need of the novel and effective drugs. Meanwhile, carbapenem-resistant P. aeruginosa strains located at the first line of the emergency. Currently, both monotherapy and combination therapy are used for the treatment, but they are not always effective. One of the major reasons for the failure of treatment is the severe antibiotic resistance of P. aeruginosa. In addition to the inherent antibiotic resistance of this bacterium, it can also receive the antibiotic resistance gene from its environment. Also, the role of genetic mutations and improper use of antibiotics should not be underestimated in these kinds of resistances. There is another considerable point about antibiotic resistance of P. aeruginosa, which is its ability to the formation of recalcitrant biofilm and persister cells. Over time, several antibiotics have been used to treat P. aeruginosa, but unfortunately, they have lost their healing power one after another. Penicillin, aminoglycosides, third generation of cephalosporin are examples of these antibiotics. Imipenem and meropenem are currently being used to treat P. aeruginosa severe infections. But, resistance to both of them is also increasing. Unfortunately, many P. aeruginosa strains have also been identified that are resistant to all available antibiotics. Nevertheless, researchers are trying to find new drugs and they have partly succeeded. Some newly introduced antibiotics include plazomicin, doripenem, and POL7001. Anyway, we still need novel and more effective drugs against P. aeruginosa infections.

Toxin-antitoxin (TA) systems are found in large numbers in the bacterial genome. They were even seen as multiple copies in most cases. Structurally, TA systems are encoded by two or more adjacent genes that are expressed toxin and its cognate antitoxin elements all together. Generally, antitoxin neutralizes its cognate toxins and thus controls TA system functions. All toxins are protein elements while antitoxins can be proteins or non-coding RNAs. Hitherto, six types of TA systems are considered based on structural features and mode of action. Type II is more attractive to researchers due to its high frequency. Scientists believe that TA systems are involved in key biological functions due to their regulatory properties. Therefore, several crucial features have been proven for TA systems including, biofilm formation, persister cell formation, antibiotic resistance, programmed cell death, plasmid maintenance, etc. Since these systems are abundant, regulatory, and involved in the biology of bacteria, they have been studied as potent antimicrobial targets. The purpose of writing this chapter is to acquaint the reader with the different aspects of these systems to become more familiar with TA systems importance and performance.

Toxin-antitoxin systems have been identified in most bacteria and archaea that preservation of bacterial or archaeal population is their ultimate goal. Indeed, they are regulatory systems, which play an important role in bacterial pathogenesis as well as regular physiological processes. Although they have been assigned many vital roles (antibiotic resistance, biofilm formation, persister cell formation, plasmid maintenance, post segregational killing), their role in each bacterial species is unique. Among bacterial pathogens, P. aeruginosa is of great importance due to its high pathogenicity. Here, we described the most known toxin-antitoxin systems and their roles in the pathogenesis of P. aeruginosa. Although bioinformatics studies have presented a large number of them, we have described those TA systems that have been confirmed by molecular tests. Acquaintance to TA systems and their role in P. aeruginosa will help to find novel ways of treatment.