Will this be the next generation of antimicrobials?

Will this be the next generation of antimicrobials?

By Pooja Bhardwaj

Antabio, a French biopharmaceutical company, is developing novel technologies to combat antibiotic resistance and address life-threatening infections. They are designing the next generation of antimicrobials by combining inhibitors against bacterial enzymes and antibiotics to improve their efficiency and defeat resistant bacteria.

The rise of the superbugs:

A major healthcare challenge in the 21st century is the rise of antibiotic-resistant pathogens or superbugs in hospitals. These resistant pathogens are a significant cause of health concern since they can result in deadly infections and treatment-failure due to the unavailability of new antibiotics that could replace the currently used medications. Furthermore, these infections add substantial financial costs to treatment regimes.

The rate at which pathogenic bacteria are developing resistance to antibiotics is shocking, and is translating into an increasing number of deaths. The Centers for Disease and Prevention (CDC) reports that in the USA at least 2 million people become infected with antibiotic resistant bacteria, at least 23,000 people die due to these infections, and warns that proper measures need to be taken to control the rate of infections caused by drug-resistant bacteria. A review published in 2016 estimates that antimicrobial resistance could cause 10 million deaths per year by 2050.

What makes these bacteria resistant?

Many factors contribute to the development of resistance The two major causes that make antibiotics ineffective are:

  1. Bacteria can rapidly evolve or acquire genes to produce counter-enzymes and degrade antibiotics.
  2. Bacteria can multiply in huge numbers and form a protective layer, known as a biofilm, so that antibiotics are unable to reach them.

How to defeat antibiotic-resistant bacteria?

Researchers are working on different strategies against this worldwide public safety threat. In the past few years, phage therapy has received revived attention due to its high specificity and ease of isolation. Phage cocktails targeting several different bacteria are an appealing alternative to antibiotics. In addition, computational methods are being used to accelerate drug discovery. Researchers are considering alternative treatments as well; for example, the natural healing properties of honey could make it an attractive option against bacteria, and antimicrobials from cockroaches’ brains have shown positive activity against disease-causing bacteria.

The different strategies look promising, however, have certain limitations to be an effective solution for this unmet problem. For example, phages have a narrow host range and bacteria can rapidly evolve resistance to phages. Also, it is only a matter of time when bacteria can evolve resistance to a combination of antibiotics after repeated exposures. To meet the urgent medical needs of patients, the technology discussed below aims to treat chronic hospital infections by blocking the virulence or disease-causing ability of the pathogenic bacteria. Since the targets are essential for bacteria, it is difficult to evolve resistance against them.

Metalloenzyme inhibitors and antibiotic combinations against resistant bacteria:

Researchers at the French biopharmaceutical company, Antabio are developing the next generation of antibacterials to fight the antibiotic-resistant bacteria responsible for serious infections in hospitals. They are creating an inhibitors pipeline against commonly found enzymes in bacteria known as metalloenzymes, which are essential for bacterial survival and pathogenesis. The principle is based on combining these inhibitors with existing antibiotics and exploiting their synergistic activity to kill bacteria.

This combination therapy will resensitize the resistant bacteria to antibiotics and improve killing efficiency. The team at Antabio is currently dedicated to treating infections caused by Gram-negative bacteria, such as  Escherichia coli by targeting metallolactamases, popularly known for degrading penicillin-like beta-lactam antibiotics, and Pseudomonas aeruginosa in chronic cystic fibrosis infections by inhibiting elastases, which are essential for bacterial virulence in the patients’ lungs.

The company has received financial support (up to $8.9 million) to accelerate its drug discovery and development programs by CARB-X. It has also received two awards from the Wellcome Trust for €4.7 million and €4.0 million in 2013 and 2015 respectively. Antabio which started its first crowdfunding in 2011 has collaborated with different groups over the past six years to introduce the safe and potent next generation of antimicrobials in the clinic by 2019. The fast-track marketing approval is expected by 2023.

Due to the specificity of inhibitors against the metalloproteinases, the technology is expected to have fewer off-target effects and decrease the doses of antibiotics required, hence making it novel, safe, and efficacious. This, in turn, poses less risk to healthy gut microbes in patients, increases the chances of speedy recovery, and reduces treatment costs.

Challenges in metalloenzyme inhibitors and antibiotic therapy:

Metalloenzyme inhibitors have been previously proposed for wide applications, but most do not possess effective in vitro and in vivo antimicrobial properties. Antabio’s current drug pipeline is showing positive results against Enterobacteriaceae resistant to a type of beta-lactam antibiotic, carbapenem, in animal infection models.

The current challenge Antabio is facing in bringing their next generation of antimicrobial therapies to market is to seek fast regulatory approval by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). The metalloenzyme inhibitors will need to prove highly selective, well-absorbed, and effective, as well as stable in the presence of other metalloenzyme inhibitors and in vivo. Another challenge is administration of safe doses in patients without eliciting immune responses. Finally, aside from regulatory hurdles, there is the ever-present threat that the bacteria could evolve rapid resistance to the metalloenzymes inhibitors.

 If Antabio is capable of quickly advancing their metalloenzyme inhibitor through clinical trials, their therapy could give doctors a major advantage in the ongoing fight against antibiotic-resistant superbugs.

Interested in exploring more novel technologies being developed to fight drug-resistant bacteria? Feel free to reach out to Charles Wright (cwright@prescouter.com), PreScouter Project Architect and medical industry thought leader. 

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