Immuno-antibiotics: A New Frontier in the Fight Against Antimicrobial Resistance

Almost a century after the discovery of penicillin, an estimated 700,000 people die each year due to antibiotic-resistant infections such as tuberculosis and malaria, a number that could reach 10 million by 2050.

Because of the widespread use of antibiotics in agriculture and intensive farming to promote growth and prevent disease, more resistant bacteria are transferred to people and escape into the environment.

Without effective antibiotics, routine medical procedures could become risky, common bacterial diseases that used to be easily treatable are turning into serious threats, and others we considered long gone are coming back from the past.

Just imagine life in the pre-antibiotic era where a simple infection from a cut could kill you.

Not to mention the economic burden to patients and the health care system. In 2006, hospital-acquired sepsis and pneumonia cost the U.S. health care system more than $8 billion. If the AMR crisis is not solved by 2050, the estimated cost to the global economy will run into $100 trillion.

In the last two decades, only a few new antibiotics have been approved for clinical use and resistant bacteria have already emerged against these new drugs. The number of new molecules in the pipeline has been on the rise since 2014, but to stop resistant bacteria in their tracks we need creative, out-of-the-box solutions that are less likely to be circumvented.

The lab of Dr. Farokh Dotiwala at The Wistar Institute Vaccine & Immunotherapy Center recently reported a landmark discovery that could lead to the development of a new class of antibiotics, built on the idea that if we attack bacteria on multiple fronts, they are less likely to find a way out and become resistant.

Nature, one of the highest impact scientific journals, published the study and then highlighted it with a commentary in Nature News & Views, a scientific forum that discusses influential and broad-interest studies, as a highly promising proof of concept for an innovative strategy for tackling the emergence of drug resistance.

World Health Organization leaders "tweeted" about the importance of immuno-antibiotics to their more than million followers.

Dotiwala and his team reasoned that vaccines are much less likely to give rise to resistance because they work by enlisting the body’s immune response rather than just directly killing the pathogens (like traditional antibiotics do). So, they researched an antibacterial strategy that could also harness an immune response.

The new compounds, named immuno-antibiotics, kill bacteria by blocking a metabolic pathway that is essential for them to grow and survive. Though at the same time, these drugs potently activate a subset of T cells involved in immune responses to a wide variety of viral and bacterial infections, adding a second line of attack.

When tested on patient-derived, drug-resistant bacteria and in preclinical models of infection, immuno-antibiotics outperformed the current best-in-class antibiotics.

Creating a synergy between the direct killing of antibiotics and the natural power of the immune system, immuno-antibiotics have the potential to represent a milestone in the fight against AMR.

The Bacteria Whisperer: Bacterial Chatter and Antibiotic Resistance

Antibiotic-resistant bacteria keep Dr. Bonnie Bassler up at night. The Princeton molecular biologist who made groundbreaking discoveries demonstrating that bacteria communicate and orchestrate group behaviors has dedicated her life to unraveling how these tiny, primitive beings exert so much power in the world.

"Microbes are what kill most people on earth,” Bassler said. “Yet the world does not appreciate how vulnerable we are to pathogenic microbes."

She considers COVID-19 a wakeup-call. We need to study microbes and make arsenals of therapeutics to fight infectious diseases. “The mindset that it’s passé to be working on antibiotics needs to change,” she added.

Bacteria can talk to each other and are capable of collective behaviors

Bassler’s work changes the way we think about bacteria and has opened up new avenues to fight them. We’ve known about the existence of bacteria for 500 years, but scientists thought of them as asocial, single cells. Thanks to Bassler’s research, we now know that bacteria can talk—distinguish self from other and act in groups—behaving like multicellular organisms that collectively assess the surrounding world and manage tasks in unison.

That’s how pathogenic bacteria make us sick and how beneficial bacteria make higher organism life possible.

The human body is inhabited by trillions of bacteria. There are 10 times more bacterial cells than human cells in and on us and, as a consequence, 100 times more bacterial genes than we have human genes. “Our own genomes do not have the capacity to do some of the things bacteria do,” Bassler noted. In essence, these 24/7 partners of ours sort of make us who we are.

How do they do that? 

They use a chemical language to communicate and monitor the environment for the presence of other cells, of similar and different species, and they even count how many cells there are in the neighborhood to determine when their population density reaches a critical mass — hence the definition of quorum sensing. Through quorum sensing, it becomes beneficial to enact group behaviors by turning on specific genes in synchrony.

Bassler’s team identified the chemical "words" in the bacterial language and discovered how these molecules mediate bacterial communication to control bacterial behavior. Bassler’s group discovered that each bacterial species has its own chemical language, that is, a private, secret language that only they understand. Bacteria also make another universal molecule that allows cross-species communication, a bacterial Esperanto, as Bassler called it.

Using quorum sensing to make antibiotics

As it turns out, the incredible phenomenon that Bassler described in elegant detail is not restricted to the obscure marine bacteria in which it was first described, but it’s the norm in the bacterial world. One group behavior frequently controlled through quorum sensing is virulence — the collective release of toxins that make the host sick — and another is the ability of bacteria to grow on surfaces and build slimy communities called biofilms, which protect cells from antibiotics and the host immune response.

Based on these discoveries, Bassler and other scientists asked themselves whether they could tinker with quorum sensing to disarm pathogenic bacteria or potentiate the action of beneficial bacteria that populate our microbiome.

"Anti- and pro-quorum sensing strategies already exist in the natural world and have been tried and tested over evolutionary time," she added. "We can use the strategies bacterial already evolved as inspiration for our studies, bringing them into the lab to refine them."

Hope for the future

What gives Bassler hope is that scientists are resilient, creative and can come up with new strategies to fight against microbes. Just like how scientists have created vaccines in only a year for the virus that causes COVID-19.

Wistar scientists are doing their part researching innovative antibiotic strategies that attack bacteria on different fronts and harness the power of the host immune system to avoid resistance.

Hopefully, these approaches will give us antibiotics 2.0 to defeat the superbugs that have become resistant to traditional antibiotics and are now threatening global health.