바이오스펙테이터

바이오스펙테이터 Joungmin Cho 기자

These pipelines are totally different from conventional ones in targeting method and MOA

iNtRON Biotechnology disclosed its three antibiotics in clinical development. These antibiotics are totally different from conventional ones in targeting method and mode of action. They have antibacterial activities against bacterial strains that are resistant to current antibiotics including superbugs. Therefore, World Health Organization (WHO) has classified them as new specialties.

▲Jun Soo-Youn, senior Technical Director of iNtRON Biotechnology Institute

"It can be safely said that our pipeline products have completely different working mechanisms from existing antibiotics,” said Jun Soo-Youn, senior Technical Director of iNtRON Biotechnology Institute in an event entitled ‘Biodrug Pipeline Investment Forum’ held in Yeoido, Seoul on November 15. The forum was co-organized by Korea Biotechnology Industry Organization and Mirae Asset Daewoo.

“Now that these products have been developed for the first time in the world, they have been classified as new-class antibiotics after WHO screening, with a new nomenclature of “-bacase’ in ending. iNtRON is a global forerunner that develops lead antibiotics.

In the forum, Director Jun elaborated three antibiotics, including endolysin-based 'SAL-200' against Gram-positive bacteria, protein drug 'itLysin', and small-molecular drug 'Axakacin' against Gram-negative bacteria.

Conventional antibiotics interfere with the replication and transcription of DNA in bacteria cells and inhibit the production of RNA. In contrast, iNtRON has studied bacteriophage-derived endolysins produced during last stages of phage infection. They are designed to attack the peptide-glycan (PG) layer that holds bacterial cell wall together by hydrolysis.

Director Jun said that "Endolysins are enzymes used by bacteriophages at the end of their replication cycle to degrade the PG layer of bacteria. We are focusing on recombinant engineering to optimize endolysins for medical applications."

"Unlike cells of the host, bacteria have a specific PG layer that poses a formidable barrier. Hitting the PG layer as a new antibiotic target will result in less cell damage and side effects".

Six Gram-positive genera of bacteria are known to cause serious diseases in humans. Of these, Staphylococcus aureus is one of the typical pathogens. Superbacteria have developed resistance to many antibiotic drugs. They are also frequently found in S. aureus. iNtRON’s biodrug 'SAL-200' offers extraordinary efficacy in infections caused by S. aureus. In in vitro microscopic tests performed by incubating S. aureus in the medium treated with SAL-200, researchers found that the drug disrupted the cell membrane of S. aureus within several seconds, thus killing the bacteria. For efficacy comparisons, SAL-200 exhibited better bactericidal activity than other antibiotics.

Director Jun said that "Following GLP-compliant toxicity study, Phase I clinical trial revealed no adverse reactions associated with SAL-200 treatment in 36 healthy adult volunteers. Further, desired plasma concentrations of SAL-200 were maintained during predetermined time points. Phase II clinical trial for patients with S. aureus is now under way in two different hospitals: Seoul National University main Hospital and its Branch Hospital in Bundang.

Director Jun also introduced other antibiotics against Gram-negative bacteria (itLysin and Axakacin). To date, iNtRON has secured five different candidate compounds that are effective for Pseudomonas and E.coli after intensive endolysin-based screening.

Director Jun stated that "Gram-negative bacteria are more resistant to antibiotics because their outer membrane comprises a complex lipopolysaccharide (LPS) whose lipid proportion acts as endotoxin. Therefore, we are developing ideal antibiotics with potential ability to bind to both LPS and PG layers". She added that the company’s proprietary platform based itLysin has yielded favorable outcomes.

In addition, a small-molecular antibiotic Axakacin, a modified version of amikacin, has drawn keen attention from participants.

Director Jun said that "The amine group (-NH2) of amikacin is disrupted by enzymatic modification, thus exhibiting amikacin resistance. Since we substituted the amine group with a hydroxyl group (-OH) in Axakacin, efficacy remains unchanged without drug resistance".

When minimum inhibitory concentrations (MIC; the lowest concentration of a chemical which prevents visible growth of a bacterium) were compared between amikacin and aminoglycosides (amikacin, gentamicin), Axakacin exhibited enhanced effects by 30-fold. The company is now developing its manufacturing process at industrial scale. It is also preparing safety and efficacy data compliant to international standards.

Director Jun emphasized that "With multi-drug resistant cases increasing globally, better antibiotic drugs and novel drug-targets are urgently needed. Our competitiveness in bacteriology is that iNtRON’s novel antibiotics have fundamental different modes of action with better antibacterial activities for target pathogens, irrespective of the presence of drug resistance”.