Innovative approach targets drug-resistant bacteria with new antibiotic, research reveals
Scientists have created a groundbreaking antibiotic that effectively targets and treats drug-resistant bacteria, offering hope in the fight against deadly infections
Researchers have announced the creation of a novel antibiotic specifically designed to combat resilient bacteria that are impervious to existing antibiotics, resulting in high mortality rates among individuals suffering from severe infections. The bacteria in question, Acinetobacter baumannii, is known to cause grave infections in the lungs, urinary tract, and bloodstream. This pathogen has developed resistance to carbapenems, which belong to a category of potent broad-spectrum antibiotics, as reported by the US Centers for Disease Control and Prevention.
Carbapenem-resistant Acinetobacter baumannii, also called CRAB, was ranked as the number one antibiotic-resistant "priority pathogen" by the World Health Organization in 2017. In the United States, the CDC's most recent data reported an estimated 8,500 infections in hospitalized patients and 700 deaths caused by this bacteria that year.
CRAB is responsible for approximately 2% of infections in US hospitals, but is even more prevalent in Asia and the Middle East, where it accounts for up to 20% of infections in intensive care units worldwide.
The bacteria flourishes in healthcare settings such as hospitals and nursing homes. Those at the greatest risk of infection are individuals with a catheter, on a ventilator, or with open wounds from surgery.
Harvard University and Hoffmann-La Roche researchers announce the development of a new antibiotic designed to combat the highly resistant Acinetobacter baumannii bacteria.
The researchers point out in their study, published in the journal Nature, that the pathogen is extremely challenging to eradicate, with the US Food and Drug Administration not having approved a new class of antibiotic for its treatment in over 50 years. However, the researchers from Harvard University and Swiss health care company Hoffmann-La Roche have discovered that the new antibiotic, Zosurabalpin, is capable of effectively eliminating Acinetobacter baumannii.
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Dr. Kenneth Bradley, the global head of infectious disease discovery at Roche Pharma Research and Early Development, and his team of researchers have discovered that Zosurabalpin is in its own chemical class and has a unique method of action.
"This is a novel approach, both in terms of the compound itself and the mechanism by which it kills bacteria," he said.
Acinetobacter baumannii is a type of bacteria that has a double membrane, making it hard to treat. The research aimed to find a molecule that can penetrate the double membranes and effectively eliminate the bacteria.
"The presence of these two membranes makes it challenging for antibiotics to penetrate," Bradley explained.
The research team started the development of zosurabalpin by investigating approximately 45,000 small antibiotic molecules known as tethered macrocyclic peptides, pinpointing which ones could effectively hinder the growth of various bacteria. Through years of enhancing the effectiveness and safety of a select few compounds, the researchers eventually identified one altered molecule.
Zosurabalpin works to halt the growth of Acinetobacter baumannii by obstructing the transportation of crucial large molecules, lipopolysaccharides, to the outer membrane. These molecules are necessary for maintaining the integrity of the membranes, ultimately resulting in the death of the bacterial cells.
The research found that Zosurabalpin was successful in combating over 100 CRAB clinical samples. The antibiotic significantly decreased bacterial levels in mice with CRAB-induced pneumonia and prevented the death of mice with sepsis caused by the bacteria.
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The researchers stated that targeting harmful Gram-negative bacteria in drug discovery has been a persistent challenge due to the complexities of penetrating bacterial membranes to reach cytoplasmic targets. They also noted that successful compounds need to have specific chemical characteristics. The study authors reported that Zosurabalpin is currently in phase 1 clinical trials to evaluate its safety, tolerability, and pharmacology in humans.
Dr. Michael Lobritz, global head of infectious diseases at Roche Pharma Research and Early Development, emphasizes that despite new developments, antimicrobial resistance continues to pose a significant global public health threat due to the lack of effective treatments. This occurs when bacteria and fungi evolve to survive encounters with drugs designed to kill them.
Approximately 1.3 million people globally lost their lives due to antimicrobial resistance in 2019, as reported in a 2022 analysis by the Lancet. In comparison, HIV/AIDS and malaria caused 860,000 and 640,000 deaths, respectively, during the same year.
In the United States, there are over 2.8 million cases of antimicrobial-resistant infections annually, resulting in more than 35,000 deaths, as stated in the CDC's 2019 Antibiotic Resistance Threats Report.
Lobritz explained that in the past few decades, there has been an increase in the development of antibiotics specifically designed to treat Gram-positive infections, which are generally less harmful and more susceptible to antibiotics than Gram-negative bacteria.
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"Gram-negative bacteria have been developing resistance to our top antibiotics for quite some time," he explained, and zosurabalpin is the only antibiotic that can combat this "very strong" pathogen.
The researchers suggest that the method employed to suppress the growth of Acinetobacter could be beneficial for other difficult-to-treat bacteria such as E. coli. "It operates by preventing the formation of the outer membrane," Bradley explained, noting that this mechanism is common among all Gram-negative bacteria. By comprehending the biology of this process, upcoming researchers may discover how to impede the growth of other bacteria using various modified molecules.
Lobritz noted that innovations are difficult to achieve, adding that it has taken 10 years of dedicated effort to bring the project to its current state. However, there are still more clinical trials needed to determine its efficacy as a medicine.
