New Antibiotic May Cure and Prevent E. coli O157:H7 Infection

2011-11-21 16:03

A new antibiotic that may cure as well as prevent infection from E. coli O157:H7 is the topic of a recent scientific study published in the journal Antimicrobial Agents and Chemotherapy. What makes this E. coli O157 antibiotic novel is that it takes advantage of a key antibacterial protein complex that some types of bacteria secrete to kill off competing bacteria. The study demonstrates that this new antibiotic delivered orally in experimental rabbits before and after bacterial exposure and infection with E. coli O157 resulted in prevention and recovery from a bacterial disease that infects approximately 73,000 people annually in the U.S.

Treating an infection from the bacterium E. coli O157 is problematical in two ways. The first way is that treatment with some antibiotics often makes the patient increasingly ill. When an antibiotic kills the bacteria, the bacteria then releases toxins that cause severe diarrhea and intestinal inflammation. Another complication is that the antibiotic may also kill off beneficial bacteria that the gut needs to maintain a healthy microbial environment.

Researchers working in collaboration with the biotech company AvidBiotics—a research facility that focuses on developing antibacterial proteins as an alternative to traditional antibiotic drugs—believe that they have found a solution to the aforementioned problems. Their solution is to take advantage of a protein complex that some strains of bacterial secrete to kill off competing bacteria within a shared environment. The protein complex is referred to as “R-type pyocins,” which basically are high molecular weight particles that have bacteria-killing abilities.

R-type pyocins are derived from a particularly nasty type of bacteria called “Pseudomonas aeruginosa” (P. aeruginosa), that according to scientists are able to infect just about anything that lives. It is a free-living, gram negative bacterium, commonly found in soil and water and is one of the few types of bacteria that are considered to be true pathogens of plants. However, P. aeruginosa is also recognized as an emerging opportunistic pathogen of humans, particularly in clinical settings as a source of antibiotic resistant, nosocomial (in hospital) infection.

P. aeruginosa causes a wide range of infections in patients with severe burns, and in cancer and AIDS patients who are immunosuppressed. The infections include urinary tract infections, respiratory system infections, bacteremia, bone and joint infections, gastrointestinal infections dermatitis, soft tissue infections and systemic infections. The fatality rate in immunocompromised patients with P. aeruginosa infection is approximately 50 percent. According to the CDC, P. aeruginosa is the fourth most common hospital infection and is responsible for about 10 percent of all nosocomial infections. However, there is a good side to P. aeruginosa. As it turns out, some strains of P. aeruginosa are deadly to other types of pathogenic bacteria.

Like humans, bacteria are also susceptible to infection by viruses. Viruses that attack bacteria are called bacteriophages. The hypothesis is that many years ago, some bacteria types were able to engulf bacteriophages and subsequently incorporate some sections of virus DNA into the bacterium’s DNA. One of the hypothesized sections of virus DNA that was incorporated by the bacteria DNA was that which made up the tail section of a virus. The tail section of a virus plays an important role in recognizing, adhering to and infecting a bacterial or human cell.

These virus tail sections of DNA, now part of the bacterium’s DNA, code for modified R-type pyocins that resemble and act a lot like a virus’s tail. An R-type pyocin has 4 major parts to it. The first part is a rod shaped body called a sheath that holds within its interior a core that is like a drill bit or spear tip that can penetrate a bacterium’s cell wall. The base of the body has a baseplate from which the core projects, and that possesses multiple tail fibers. The tail fibers are like feelers or sensors that can recognize specific chemical groups on a bacterium’s surface, which essentially allows the pyocin to recognize a specific bacterium as a foreign competitor that needs to be killed.

The end result is that a bacterium that codes for R-type pyocin can secrete pyocin particles that recognize invading bacteria, bind to their cell surfaces and physically stab the bacterium—not unlike a virus injecting its genetic material into a bacterial cell during infection. In the case of the pyocin, however, there is no genetic material injected. Rather, the stab results in creating a hole in the bacterial cell wall, causing some of cell’s contents to spill out leading to the bacterium dying.

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AvidBiotics’ researchers have taken advantage of the bacteria-killing ability of pyocin particles by engineering modified tail sections that will recognize and bind to strains of E. coli O157:H7 bacteria. In their study, they tested the effectiveness of their modified pyocin constructs (called AvR2-V10.3) on experimental rabbits that were treated both before and after infection with E. coli O157:H7. What they found is summarized as follows:

• The pyocin protein AvR2-V10.3 remained active within the treated animals’ intestinal tract for at least 24 hours following administration.

• When given shortly after the animals were infected with E. coli O157:H7, but before developing into a diseased state, the pyocin protein inhibited bacterial colonization and/or the symptoms of infection. Experimental rabbits that received the highest dose of protein did not develop diarrhea. In contrast, control rabbits given a placebo developed typical diarrhea within 1-2 days after infection.

• Analyses of colon tissue showed less severe intestinal inflammation in the pyocin protein AvR2-V10.3 treated-rabbits in comparison to the control rabbits. The pyocin treatment also greatly reduced the number of E. coli O157:H7 recovered from the intestine and the stool of treated animals.

• When the pyocin protein was fed to E. coli O157:H7-infected rabbits already exhibiting disease symptoms, the existing diarrhea began to resolve in treated animals compared to animals treated with placebo that continued to experience diarrhea.

The conclusion of the study by the researchers was that their pyocin particles with the modified tails to recognize E. coli O157:H7 clearly demonstrates promise as a prophylactic and therapeutic novel type of antibiotic. Not only do the modified pyocin particles prevent and cure infection, but they also do not cause toxin release when bacteria are killed and they do not target beneficial bacteria in the gut while seeking and destroying E. coli O157:H7 bacteria.

According to Dean Scholl, Ph.D., lead author of the publication, "These findings suggest that an Avidocin protein [AvR2-V10.3] targeted against E. coli O157:H7 offers promise for both the prevention and treatment of infection by this important enteric pathogen," concluded Dr. Scholl. "Moreover, this agent provides several significant advantages over conventional antibiotics, including a lack of drug-induced shiga toxin production and unintended collateral damage to normal intestinal bacterial populations.”

Reference: Antimicrob. Agents & Chemother. December 2011 vol. 55 no. 12 5469-5474

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