Figure 1. The proposed shut-down of gastrointestinal defences in Shigella infection and reversal with one of Akthelia’s active ingredients.
Antimicrobial peptides (AMP’s) are our first line of defence against invading microorganisms. They are found on all surfaces of the body, including the skin, eyes, lungs, gut and urinary tract. The human body produces multiple different antimicrobial peptides with varied structural features and specificities. The antimicrobial peptides kill the bacteria primarily by destroying the bacterial membranes. The peptides join forces, thus forming an effective and broad frontline defence mechanism that the bacteria must overcome in order to infect humans.
Importantly, virulent strains of bacteria (professional pathogens) are able to turn off the synthesis of the antimicrobial peptide arsenal (Figure 1), thus causing infections. Akthelia has identified active pharmaceutical ingredients (APIs) which are capable of inducing the synthesis of the peptides and thus counteract the effects of the bacteria. Akthelia is committed to developing these agents into therapeutic drugs.
The proposed antimicrobial treatment is a paradigm shift in the treatment of infections. At pharmacologically relevant concentrations the active ingredients have minimal direct effects on the microbes. The therapeutic effect is manifested when the active ingredient interacts with a viable epithelium, which in turn increases the production of AMPs - the true microbicidal agents. A very important and beneficial feature of this novel treatment method is the low probability of microbial resistance since with the many different peptides induced there is no single solution for the bacteria to avoid destruction. This is in sharp contrast to classical antibiotics where natural selection enriches for the resistant microbial population.
Efficacy in various models
Akthelia’s scientists have demonstrated that certain virulent bacteria severely reduce the host’s AMP defence system during infection and thereby promote pathogenicity. Akthelia has demonstrated that rabbits recover rapidly from life-threatening gastro-intestinal infections when treated with selected API’s, whereas animals in the placebo control group remain morbid or died. These studies also demonstrated rapid elimination of the pathogenic bacteria in stool. Furthermore, the treatment of human dysenteric patients with one of the pharmaceutically active substances identified by Akthelia indicates a promising outcome. Most importantly, a clinical study performed on tuberculosis patients showed that inclusion of one of Akthelia’s actives in the treatment regimen resulted in faster recovery and clearance of bacteria in sputum than in the control group. Akthelia’s actives do this without causing inflammation.
Recent studies indicate that certain antibiotics negatively affect the synthesis of antimicrobial peptides, thus providing a mechanism for opportunistic infections. Akthelia’s actives should replace these antibiotics or be included in the therapeutic regimen to reduce the chance of opportunistic infections.
Akthelia aims at developing broad spectrum, highly effective pharmaceuticals for the treatment of infections. The most important targets are virulent bacterial infections where conventional antibiotic treatment has proved ineffective. Currently, Akthelia focuses on lung infections induced by Pseudomonas and resistant Klebsiella.