HOME

ABOUT

CONCEPT

NEWS

TEAM

JOBS

CONTACT

 

BMBF Link

 

BMWi Link

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.

The rising threat

With the emergence of multidrug resistant bacterial pathogens, infectious diseases pose once again a major threat to human health. Excessive use of readily available antibiotics exerts a paramount selective pressure that rapidly leads to evolutionary adaptation of pathogenic bacteria. Nowadays resistant stains have been reported for virtually every antibiotic on the market and resistances are spreading exponentially. The known antibacterial targets however are limited and many of them have been exhaustively exploited. Thus the development of novel antibiotics has declined: only two novel antibiotics were approved and released to the market within the past 10 years. However, resistances already have emerged for both of them. Due to lacking treatment options, multidrug resistant pathogens started to become a serious problem.

AVIRU’s innovative strategy

AVIRU utilizes novel structures (patent application pending). 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 our first lead structure AVU1, we 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.
In short: the bacteria were disarmed. 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.

Technology without limits

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

Ref.: T. Böttcher, S. A. Sieber, β-Lactones as Privileged Structures for the Active-Site Labeling of Versatile Bacterial Enzyme Classes, Angew. Chem. Int. Ed. Engl. 2008, 47, 4600 – 4603; T. Böttcher, S. A. Sieber, β-Lactones as Specific Inhibitors of ClpP Attenuate the Production of Extracellular Virulence Factors of Staphylococcus aureus, J. Am. Chem. Soc. 2008, 130, 14400 – 14401; T. Böttcher, S. A. Sieber, Structurally refined β-lactones as potent inhibitors of devastating bacterial virulence factors, ChemBioChem 2009, 10, 663 – 666.