AVIRU GmbH is a spinoff from the Center for Integrated Protein Science Munich excellence cluster and its laboratories are located at TUM in Garching. The company specializes in developing small molecules to fight bacterial pathogens and parasites. The demand for alternative therapies to antibiotics is rapidly increasing. For decades, the spread of resistance and multi-drug resistant pathogens (e.g., MRSA) have threatened the efficacy of traditional antibiotics. AVIRU combats this lack of new treatment approaches with novel active ingredient candidates and a revolutionary mechanism of action.

A novel strategy was developed to counteract the increasing problem of almost untreatable bacterial infections caused by multidrug resistant pathogens. Applying β-lactones of the AVU generation to bacteria led to the discovery of the first potent inhibitor of the virulence regulating protease ClpP. Inhibition of ClpP disarmed the bacteria by a shut-down of their virulence factor expression. This offers entirely new treatment options with only minor chances of resistance development. AVIRU utilizes novel structures. These were found to selectively inhibit ClpP, a serine protease that was reported to be crucial for the virulence of several key pathogens.  The role of ClpP has been especially well studied in the opportunistic pathogen Staphylococcus aureus which made headlines in last years due to the explosive spread of antibiotic resistant (MRSA) and highly aggressive strains. The role and importance of ClpP for virulence has been demonstrated by a ΔClpP mutation in S. aureus, which exhibited strongly decreased extracellular virulence and was non-infective in a mouse model. 

ClpP acts as a central regulator of virulence. The pathogens do not attack immediately; they try to hide from the immune system and wait until a critical density of bacterial cells is reached. Then ClpP degrades a repressor of toxin gene expression which up to now prevented the production of virulence factors. By doing so, ClpP switches the bacteria from “mute” to “attack” mode. The virulence factors of S. aureus comprise a diverse set of specialized proteins, enzymes and toxins. These facilitate spreading in the human organism, provide nutritional sources by degradation of host cells and enable the pathogen to escape the immune response. Selective inhibition of ClpP by a new generation of drugs may thus represent a novel strategy in the treatment of infectious diseases.

These new generation drugs are now being developed by AVIRU. With their first lead structure AVU1, they already could demonstrate a global shut down of important toxins involved in the proteolytic and hemolytic (blood lysing) activity of S. aureus but also of devastating pyrogenic toxins like enterotoxins B and C and the toxic shock syndrome toxin. These toxins are responsible for severe, often even lethal diseases including food poisoning and sepsis. This strategy was not only successful with laboratory strains of S. aureus but also with problematic multidrug resistant and highly virulent clinical isolates.

BENEFITS

A drug based on this novel concept would display several advantages: Instead of being killed, the pathogens become disarmed, but stay alive. Thus, there is no direct selective pressure that provokes the emergence of resistances. Even if there were single resistant bacteria, they could not attack and harm the host, if the majority of bacteria were disarmed. The immune response finally will eliminate these bacteria. Another advantage of not killing bacteria is that the cooperative bacteria of the human body, like in the gut flora are preserved. Their destruction by conventional antibiotics leads to undesired and often hazardous side effects. An intact microbial flora furthermore prevents the colonisation by resistant strains. This is a very serious issue after antibiotic treatments and a reason for the problem of MRSA infections. This new strategy of disarming pathogenic bacteria by inhibition of ClpP, their central regulator of virulence, thus provides a promising concept for the development of a novel drug by AVIRU.

The innovative technology of AVIRU is by far not limited to S. aureus. The target ClpP is highly conserved among key pathogens and compounds have also been shown to exhibit activity against the devastating intracellular pathogen Listeria monocytogenes and recently even against the malaria parasite.