Scientists have developed a new antibiotic that could give medicine a new weapon to fight drug-resistant bacteria and the diseases they cause. The antibiotic, cresomycin, described in Science, effectively suppresses pathogenic bacteria that have become resistant to many commonly prescribed antimicrobial drugs.
New Antibiotic : How cresomycin works
Cresomycin is the latest finding for a longtime research partnership between the group of Yury Polikanov, associate professor of biological sciences at the University of Illinois Chicago (UIC), and colleagues at Harvard University. The UIC scientists provide critical insights into cellular mechanisms and structure that help the researchers at Harvard design and synthesize new drugs.
In developing the new antibiotic, the group focused on how many antibiotics interact with a common cellular target – the ribosome – and how drug-resistant bacteria modify their ribosomes to defend themselves. More than half of all antibiotics inhibit growth of pathogenic bacteria by interfering with their protein biosynthesis – a complex process catalyzed by the ribosome, which is akin to “a 3D printer that makes all the proteins in a cell,” Polikanov said.
Antibiotics bind to bacterial ribosomes and disrupt this protein-manufacturing process, causing bacterial invaders to die. But many bacterial species evolved simple defenses against this attack. In one defense, they interfere with antibiotic activity by adding a single methyl group of one carbon and three hydrogen atoms to their ribosomes.
Scientists speculated that this defense was simply bacteria physically blocking the site where drugs bind to the ribosome, “like putting a push pin on a chair,” Polikanov said. But the researchers found a more complicated story, as they described in a paper published last month in Nature Chemical Biology.
By using a method called X-ray crystallography to visualize drug-resistant ribosomes with nearly atomic precision, they discovered two defensive tactics. The methyl group, they found, physically blocks the binding site, but it also changes the shape of the ribosome’s inner “guts,” further disrupting antibiotic activity.
Polikanov’s laboratory then used X-ray crystallography to investigate how certain drugs, including one published in Nature by the UIC/Harvard collaboration in 2021, circumvent this common form of bacterial resistance.
“By determining the actual structure of antibiotics interacting with two types of drug-resistant ribosomes, we saw what could not have been predicted by the available structural data or by computer modeling,” Polikanov said. “It’s always better to see it once than hear about it 1,000 times, and our structures were important for designing this promising new antibiotic and understanding how it manages to escape the most common types of resistance.”
How cresomycin differs from other antibiotics
One of the key features of cresomycin is that it belongs to a new class of compounds called oxazolidinones, which have a different chemical structure and mode of action than most existing antibiotics. Oxazolidinones are synthetic molecules that do not occur naturally in nature, unlike many other antibiotics that are derived from microorganisms.
Oxazolidinones work by binding to a specific site on the bacterial ribosome that is essential for protein synthesis. By blocking this site, they prevent the formation of new proteins and stop bacterial growth. Cresomycin is an improved version of an existing oxazolidinone drug called linezolid, which was approved by the FDA in 2000.
Linezolid is effective against many gram-positive bacteria, such as MRSA and VRE, but it has limited activity against gram-negative bacteria, such as E. coli and P. aeruginosa. Moreover, linezolid can cause serious side effects such as bone marrow suppression and nerve damage if used for long periods of time.
Cresomycin overcomes these limitations by having a modified chemical structure that enhances its potency and reduces its toxicity. Cresomycin can kill both gram-positive and gram-negative bacteria, including those that are resistant to linezolid and other antibiotics. Cresomycin also has a longer half-life than linezolid, which means it stays longer in the body and requires less frequent dosing.
Why cresomycin is important
The development of cresomycin is a significant breakthrough for the field of antimicrobial research, which faces the challenge of rising antibiotic resistance among many bacterial pathogens. According to the World Health Organization (WHO), antibiotic resistance is one of the biggest threats to global health, food security and development today.
Antibiotic resistance occurs when bacteria change in response to the use of antibiotics and become able to survive or grow despite exposure to drugs that are meant to kill or inhibit them. This reduces the effectiveness of antibiotics and makes infections harder to treat.
Some of the most common infections caused by drug-resistant bacteria include urinary tract infections (UTIs), pneumonia, tuberculosis (TB) and gonorrhea. These infections can lead to serious complications such as sepsis, organ failure and death.
The WHO estimates that at least 700,000 people die each year due to drug-resistant infections, and this number could increase to 10 million by 2050 if no action is taken. The economic cost of antibiotic resistance is also enormous, as it reduces productivity and increases health care spending.
Therefore, there is an urgent need for new antibiotics that can overcome bacterial resistance mechanisms and restore the effectiveness of existing drugs. Cresomycin is one such antibiotic that has shown promising results in laboratory tests against several drug-resistant bacteria, such as E. coli , K. pneumoniae and P. aeruginosa , which are responsible for many hospital-acquired infections.
The researchers hope that cresomycin will soon enter clinical trials and become available for human use in the near future. They also plan to continue their collaboration and explore other potential targets for new antibiotics that can combat bacterial resistance.
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