First antibiotic in 50 years to tackle superbug nears approval: what’s going on in the field?

For the first time in 50 years, a new antibiotic has been created to tackle a drug-resistant bacteria that causes serious infections like pneumonia and sepsis. While antibiotic development has seen a slump in the past couple of decades, there are a few ongoing studies testing novel antibiotics – but how much of a difference will these drugs make in battling infectious diseases?

Roche’s antibiotic zosurabalpin to enter phase 3 trials

Swiss drug maker Roche hit the headlines when it announced that it is advancing the development of its antibiotic zosurabalpin into phase 3 trials. The candidate will “address the challenge of increasing antibiotic resistance,” according to Michael Lobritz, global head of Infectious Diseases, Roche Pharma Research & Early Development.

“Our goal is to contribute new innovations to overcome antimicrobial resistance, one of the biggest infectious disease challenges to public health,” said Lobritz in a statement to Labiotech.

The bacteria that zosurabalpin is targeting is a deadly Gram-negative bacteria called Acinetobacter Baumannii. Gram-negative bacteria have a thick outer layer unlike Gram-positive bacteria, making them notorious to treat, as their cell wall acts as a barrier to antibiotics and other antimicrobial agents. 

Acinetobacter Baumannii, in particular, tends to be resistant to a broad class of antibiotics, such as carbapenem. People infected with carbapenem-resistant Acinetobacter baumannii (CRAB) who suffer from invasive symptoms are at risk of dying from the infection because these antibiotics don’t work. In up to 60% of cases, invasive CRAB infections can lead to death. While scientists have been on the hunt for new drugs, efforts to tackle CRAB have been to no avail until now. 

Jointly developed with Harvard University, zosurabalpin is able to destroy CRAB’s outer membrane, specifically a protein complex called the LptB2FGC complex that transports material to the cell surface, and is ultimately necessary for the pathogen’s survival. By hindering the transport of these materials, such as lipopolysaccharide – which serves as the bacteria’s cell barrier – it prevents the formation of the outer membrane, which it relies on to live.

A phase 1 trial found the antibiotic to be safe and tolerable. This was following preclinical studies in mice with lung and thigh infections caused by drug-resistant A. baumannii that proved its effectiveness in ending infection. 

“Drug-resistant Acinetobacter are present in every country of the world and disproportionately impact patients who are in hospital, causing invasive infections like pneumonia and bloodstream infections or sepsis,” said Larry Tsai, senior vice president and global head of Immunology, Product Development at Roche. “Roche hopes that further clinical trials will demonstrate that zosurabalpin can help tackle the rising issue of antibiotic resistance and contribute to addressing a major infectious disease challenge to public health. Additionally, the innovative biology involved in this research could potentially reveal new insights into the structure of bacterial membranes, possibly leading to the discovery of new antibiotics in the future.”

The upcoming phase 3 trial will compare the efficacy of zosurabalpin with standard-of-care antibiotics in around 400 patients with CRAB infections in sites across Europe, North America, South America, and Asia. As the study is poised to begin later this year or early next year, this brings it a step closer to a potential landmark approval.

Antibiotic resistance: the biggest hurdle in addressing bacterial infections

With zosurabalpin being the first new class of antibiotics in more than half a century, this is a huge deal in antibiotic research. Back when the first-ever antibiotic was discovered – penicillin, in 1928 – it was regarded as a significant stride in treating bacterial infections. As the discovery of more and more antibiotics came to light, such as the class of drugs called aminoglycosides, which includes streptomycin for tuberculosis, curing infections became achievable. This, in turn, extended life expectancy. 

However, antibiotic resistance became a problem almost immediately after these medicines started being prescribed by doctors. According to the National Foundation for Infectious Diseases, antibiotic resistance occurs when bacteria develop defenses against the antibiotics that have been developed to kill them. And unfortunately, once people become resistant to a certain antibiotic, a different one needs to be prescribed to tackle the infection, which may not be as effective in nature. 

“Due to the rapid rate at which bacterial organisms evolve, antibiotic resistance has been documented as early as a year after the introduction of a novel antibiotic to the market, limiting the window of utilization for these medications,” said Steven Goldberg, chief medical officer (CMO) of American infectious disease testing laboratory HealthTrackRx.

When pathogens evolve, it renders many traditional antibiotic targets ineffective. This forces drug developers to identify new mechanisms to kill superbugs. This is especially the case for Gram-negative bacteria like CRAB. 

“Gram-negative bacteria present formidable challenges due to their double-membrane structure, efflux pumps, and ability to acquire resistance genes rapidly. These organisms have evolved sophisticated mechanisms that limit the entry of antibiotics and promote survival under therapeutic pressure,” said Goldberg.

He added that their outer membrane structure prevents beta-lactam antibiotics – one of the most effective antibiotic classes encompassing penicillins and cephalosporins – from working effectively, and limits antibiotic development for Gram-negative pathogens to other mechanisms of action. 

“The original antibiotics that defined the first classes and mechanisms of action were discovered from living organisms. As such, pharmaceutical innovation focused on modifying these existing chemical scaffolds rather than pursuing novel classes, in part due to technical complexity and economic disincentives,” he said.

Not enough antibiotics; is lack of funds to blame?

Moreover, antibiotic development poses “unique” economic hurdles, according to Goldberg. 

“Antibiotics often yield a limited return on investment as they are used for a short duration of therapy compared to continuous treatments for chronic diseases. These market dynamics have led to a diminished pipeline and reduced private sector interest, requiring new incentives, partnerships, and reimbursement models to bring effective agents to market,” said Goldberg.

This has partly led to many biopharmas ditching their antibiotic candidates in search of more lucrative prospects instead. By 2018, 12 major biopharmas had scaled back on antibiotic development and switched focus to treating chronic diseases and cancer. Novartis was one of them, laying off 140 employees and blaming it on the antibiotics business model. This was following AstraZeneca selling off its antibiotics unit to Pfizer. A year later, American company Achaogen, a known player in the antibiotics market at the time, filed for bankruptcy. 

Around the same time, anti-bacterial developer Spero Therapeutics lost half its market capital. And just a few months ago, a clinical trial failure led to 39% layoffs and now the Massachusetts-based company has been delisted from NASDAQ.

Even younger startups have had no luck. Massachusetts-based Octagon Therapeutics arrived on the scene bright-eyed and bushy-tailed in 2017, but soon its eagerness faded. While it managed to raise seed funding, it culled its antibiotic program and pivoted to treating autoimmunity. However, last month, its co-founder announced on LinkedIn that the company was shutting down.

WHO presses for increased antibiotic reseach and development 

While antibiotic development has picked up pace in the last couple of years, it is not enough, according to the World Health Organization (WHO). A report by WHO stated that we need to replace the antibiotics that are becoming ineffective due to widespread use. Yukiko Nakatani, assistant director-general for Antimicrobial Resistance at WHO, warned that antimicrobial resistance is only getting worse, but drugs aren’t being developed fast enough to combat deadly pathogens.

“Not only are there too few antibacterials in the pipeline, given how long is needed for research and development (R&D) and the likelihood of failure, there is also not enough innovation,” the report read.

A lack of investment in the field hurts the chances of innovation. A 2022 report by BIO claimed that why the current antibiotics pipeline isn’t diverse enough – proven by the fact that only 18% of antibiotics have been approved since 2000 – is because money is not being spent to create antibiotics in the first place, possibly because of the reasons Goldberg cited: that they are not profitable enough. 

Unlike with other therapies, wherein drug developers can bet on the sales to fuel further R&D, antibiotics can’t count on the market to do so because these medicines are used sparingly to protect public health, according to a report by the European Federation of Pharmaceutical Industries and Associations.

So, policymakers have come up with a way to draw more investment into antibiotic R&D. Health authorities have introduced pull incentives, a measure in which scientists and biotechs are rewarded once they have successfully developed an antibiotic, to renew interest in antibiotic development. 

Research related to new antibiotics:

• Deep Learning Model Discovers Antibiotic Drugs in Extinct Organisms Effective Against Drug-Resistant Superbugs – University of Pennsylvania 
• System for Producing and Delivering Targeted Antibiotics – North Carolina State University 
• Novel First-choice Last-resort Antibiotic – University of Southern Denmark

Antibiotic development: are pull incentives the answer?

“Pull incentives, mechanisms to provide a known and predictable return on investment for new antibiotics, are well established as a way to overcome this challenge and were recognised in the 2024 UN Political Declaration on AMR. However, beyond pilots, pull incentives have not been widely adopted. It is vital that these incentives are in place, which give governments the supply of new antibiotics they need and companies the certainty required to invest in research,” said Michael Oberreiter, head of External Affairs International at Roche.

With this gaining momentum across Europe, in countries like the U.K., Sweden, and Germany, clinical trials are ongoing in different parts of the world. American biotech Venatorx was awarded a $318 million contract from the U.S. Biomedical Advanced Research and Development Authority (BARDA) to develop its lead candidate cefepime-taniborbactam a few years ago.

Cefepime is a widely used beta-lactam antibiotic that works against susceptible Gram-negative and Gram-positive bacteria. When combined with taniborbactam, a beta-lactamase inhibitor, it could be used as a potential treatment option for patients with serious bacterial infections caused by antibiotic-resistant Gram-negative bacteria. 

Around 70% of people with complicated UTIs (cUTIs) were cleared of UTI-causing bacteria upon taking the drug compared with 58% of patients on meropenem, an approved beta-lactam antibiotic, marking a phase 3 win. However, the U.S. Food and Drug Administration (FDA) rejected its application for approval last year, citing manufacturing concerns. 

FDA clears Blujepa and Exblifep to treat UTIs; Acurx’s drug completes phase 2

Still, antibiotics for UTIs have received thumbs-ups from the FDA of late. Pharma giant GSK’s Blujepa, also known as gepotidacin, was cleared in March – the first in a new class of antibiotics in 30 years. This was following a phase 3 trial in women and girls aged 12 and older. Blujepa showed statistically significant superiority compared with the antibiotic nitrofurantoin. It was found to be a therapeutic success in 58.5% of people compared to 43.6% in the nitrofurantoin group. The drug will hit the market soon while GSK trials it in drug-resistant gonorrhea, another bacterial infection.

Another UTI drug that has been greenlit is Exblifep or cefepime-enmatazobactam. The German company Allecra Therapeutics-owned antibiotic was approved last year for treating a severe type of UTI called pyelonephritis, which is caused by Gram-negative bacteria.

Meanwhile, young biotechs like Acurx Pharmaceuticals are targeting specific Gram-positive bacteria, including Clostridioides difficile (C. difficile), Enterococcus, Staphylococcus, and Streptococcus. Its approach is to block a new molecular target called DNA polymerase IIIC, thereby inhibiting DNA replication, leading to Gram-positive bacterial cell death.

All of the patients who were rid of their C. difficile infection with Acurx’s lead candidate ibezapolstat remained cured after a month of finishing their dosage, according to a phase 2 trial. Now, it plans to conduct an international phase 3 study to further evaluate the oral antibiotic.

Besides, scientists in Germany have studied darobactin preclinically and want to pursue clinical trials. Researchers from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the German Center for Infection Research (DZIF) found that the genetically engineered version of the antibiotic darobactin works better than its naturally occurring counterpart. It inhibited the growth of drug-resistant bacteria like Escherichia coli and Acinetobacter baumannii in animals. 

To add to these advances, the venture capital Kineticos Life Sciences set up Kinvard Bio, a new biotech, to develop a new class of antibiotics called oxepanoprolinamides in February. This class of drugs targets bacterial ribosomes, and the newly-founded company’s pipeline is now in lead-optimization stages.

AI speeds up antibiotic discovery

Meanwhile, artificial intelligence (AI) could speed up the discovery process. Two years ago, the antibiotic abaucin was discovered using an AI-powered screening tool. The candidate was able to kill Acinetobacter baumannii in preclinical studies. Another study by scientists at the University of Pennsylvania was able to predict potential new antibiotics in the global microbiome last year.

As healthcare agencies call for more R&D in antibiotic development, specifically in tackling antibiotic resistance, pull incentives could become a potential source of motivation to create more antibiotics to battle bacterial infections. However, we are yet to see how widespread this revenue model becomes. Besides, as Roche gears up for the phase 3 trial of zosurabalpin, all eyes are on it to beat the superbug.