HOW BACTERIOPHAGES ATTACK AND KILL BACTERIA
Bacteriophages have evolved to exploit host bacteria to create progeny phages that ultimately destroy the bacterial target. Once a phage infects a host bacterial cell, it replicates itself, producing many new phages and causing the bacterium to burst, thereby releasing the remaining phages to infect and kill neighboring bacteria.
A typical phage amplification cycle takes 30-60 minutes, and only stops once the pathogenic bacteria have been eliminated. When there is nothing left for the phages to infect they are removed through the body’s natural clearance processes.
Since each strain of phage generally exploits only a particular bacterial host, phages hold the promise of delivering species-specific elimination of disease-causing bacteria while sparing non-targeted bacteria, such as those found in the beneficial microbiota.
The types of phages used by AmpliPhi kill bacteria through the following process, called the lytic cycle:
AmpliPhi’s approach potentially has several advantages compared to traditional antibacterial therapies based on the unique abilities of the lytic cycle:
Ability to Treat Antibiotic-Resistant Bacteria as well as Re-Sensitize Antibiotic-Resistant Bacteria to Antibiotics
Phages kill bacteria through a different mechanism of action than traditional antibiotics and therefore phage therapeutics are likely to be unaffected by the increasing incidence of antibiotic resistance. Phages have also been shown to re-sensitize antibiotic-resistant bacteria to antibiotics to which they were previously insensitive.
Ability to Disrupt Biofilms
Biofilms are layers of aggregated bacteria and other extracellular components that shield and protect bacteria from antibiotics. These complex communities of bacteria can render conventional antibiotics almost completely ineffective. Killing bacteria in biofilms can require concentrations of antibiotics that are up to 1000X higher than normal.
For patients, this can mean that bacterial infections involving biofilms aren’t treatable because such large doses of antibiotics could be toxic. By contrast, some phages are able to breach this defensive shield and produce a strong therapeutic effect by penetrating the biofilm and replicate locally, disrupting the biofilm and leaving the remaining bacteria exposed and vulnerable to additional phages, the patient’s immune system and available antibiotics.
Ability to Precisely Target Pathogenic Bacteria
Phage therapies are highly specific to their target bacterial strains. They cannot kill mammalian cells and have minimal impact on beneficial bacteria.
Ability for Combination Therapies
Different phages can be combined to target more than one strain or species of bacteria. Phages can also be used in combination with antibiotics, in some cases to achieve a bigger therapeutic effect than either alone.
Ability to Reduce Side Effects
Phage therapies have been administered to humans for nearly a century with few reports of serious side effects on their own. All antibiotics have side effects. Some of these, such as allergic reactions, are common and manageable. Other side effects are more debilitating, including antibiotic-associated diarrhea caused by infection with Clostridium difficile. If phages and antibiotics are used together, it may be possible to use lower doses of antibiotics and thus reduce the risk of antibiotic-related side effects.
AMPLIPHI’S UNIQUE APPROACH
Our approach for the development of product candidates is to rationally select phages that kill the most clinically-relevant bacterial strains and when combined together as a therapeutic, minimize the frequency of resistance.
AmpliPhi’s product candidates are produced at its wholly owned cGMP compliant manufacturing facility. It is believed to be the only dedicated GMP facility for phage production. This facility has produced phage therapeutics used in clinical trials and single patient expanded access cases.