Targeted antibiotics tackle bacterial resistance

Antibiotic resistance is increasing to such a level that there are fears that within 20 years antibiotics will cease to function, an eventuality that could take us back to the days before penicillin.

Compounds that block the bacteria's pathogenicity instead of killing them outright may be a solution to this confounding problem.

The lack of effective antibiotics has become more and more acute as the number of bacterial strains resistant to antibiotics has increased.

One of the companies that working on new ways to fight against the pathogenic bacteria is Creative Antibiotics based in Umeå in Sweden.

The company was founded in 2000 under the name Innate Pharmaceuticals, with the intention to commercialise research from the Univeristy of Umeå, Karolinska Institute and Univeristy of Stockholm.

CEO, Ulf Boberg, compares the company’s compounds with the targeting antibodies used to treat cancer today.

These compounds neutralise only disease-causing bacteria without harming harmless strains, just as targeted antibodies do not affect healthy cells.

“The medical industry has long hoped to cure infectious diseases by finding a common target of all disease-causing organisms. But this success has proven elusive,” says Boberg.

“Therefore we have chosen one compound that strikes against a target that exists in some disease-causing bacteria but not in all.”

The target structure he refers to is type III secretion system, T3SS, which can be likened to a trunk or a syringe, and is found in most of the gram-negative bacteria that cause disease in humans, including: Salmonella, Shigella, Pseudomonas aeruginosa, Yersinia, Chlamydia and some E. coli.

The bacteria uses this system to protect itself from the human body’s immune system.

The bacterium sticks the syringe into the immune cell when it comes into contact with the cell and it injects various toxins, which allows the bacterium to evade the immune system and to continue to infect new cells and proliferate.

Although the various gram-negative bacteria cause completely different diseases, T3SS functions in the same way in them all, which makes the structure an ideal target for new antibiotics.

These substances inhibit bacterial pathogenicity, virulence, without killing them or affecting their growth.

“There is obviously no guarantee that there won’t be resistance to these substances, but because T3SS is only present in pathogenic bacteria, the risk is considerably lower than for today's antibiotics," says Boberg.

Creative Antibiotics currently has two lead compounds in the preclinical phase. One of those is tested in two different projects: one to prevent infections in burns and the other to treat sexually transmitted diseases.

The compound, INP314, has orphan drug status in Europe and it is used for the treatment of burn patients infected with the Pseudomonas bacteria.

Since Pseudomonas also causes severe and often fatal lung infections in patients with chronic obstructive pulmonary disease, COPD, and cystic fibrosis, there is hope that the substance can be used to help these patients.

INP314 was developed in collaboration with an American research group during the project for the treatment of sexually transmitted diseases.

Studies done so far indicate the compound could block Chlamydia infection in the vagina. There are also results suggesting that the compound may have an inhibitory effect on infection with gonorrhea and herpes.

The third project with the company's virulence blocking compound is conducted under license by Indian Syngene.

The goal is to develop a treatment for diarrheal illnesses caused by Salmonella, Shigella, Yersinia or E. coli bacteria that are all present with T3SS.

The next step with all projects is to move to animal studies. If they succeed, chances are that the treatment will also be efficacious in humans, as the virulence blocking compounds strike against bacteria and not against endogenous proteins.

Boberg has high hopes that animal studies will therefore be more predictive than usual.

“The development of resistance is an enormous problem,” he says. “If the development continues as such, we are in danger of being without antibiotics in 20 years, so if we succeed, it is certainly of immense importance to society.

“I do not want to speculate on whether we will succeed with our compounds or not, but it is much too important and interesting not to be fully tested.”

Originally published in Biotech Sweden.