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With the rise in the number of drug-resistant infections and the decrease in the number of new antibiotics, the world could resort to a new strategy to fight against increasingly harsh bacteria. Stanford Chemists Report November 2 in the Newspaper Journal of the American Chemical Society a possible solution: a small molecular attachment that helps conventional antibiotics penetrate and destroy their targets.
The attachment, known as r8, helps antibiotics through the bacterium's outer defenses and encourages them to linger, said Alexandra Antonoplis, a chemistry graduate student and co-lead author with colleague Xiaoyu Zang. This penetration and toughness help kill bacteria, such as methicillin-resistant Staphylococcus aureus, or MRSA, that doctors would otherwise have trouble stopping.
Indeed, the addition of r8 to vancomycin, a frontline defense against MRSA, has made the new drug hundreds of times more effective, according to experiments conducted by Antonoplis, Zang and their advisors, Lynette Cegelski, Associate Professor of Chemistry, and Paul Wender, Professor of Chemistry Francis W. Bergstrom. The researchers believe that the same strategy could apply beyond MRSA to other drugs and infections.
"You do not have to invent a new medicine. Just fix the problems with existing drugs, "said Wender, also a member of Stanford Bio-X, Stanford Cancer Institute and Stanford ChEM-H.
The problem of MRSA
In the long run, this new approach could be good news for public health officials who have struggled to manage antibiotic-resistant infections such as MRSA. This infection, which often begins with a skin infection, accounts for more than half of hospital-acquired infections in Asia and the Americas and is the leading cause of death among antibiotic-resistant infections. .
"This is a global health problem, and we need new treatment strategies because of the growing emergence of antibiotic-resistant bacteria and the limited number of antibiotics in our pipeline," said Cegelski, also a member of Stanford Bio-X. Stanford CHEM-H. According to one report, the number of new antibiotics approved by the FDA has dropped by 90% over the last three decades. Current first-line treatment for MRSA has been used since 1958.
The antibiotic vancomycin, a first-line treatment, can prevent the spread of MRSA in some cases by preventing the construction of new bacterial cell walls, thus preventing the reproduction of the bacteria.
But vancomycin is largely useless against two of the essential defenses of the bacteria. First, MRSA tends to form biofilms, colonies of bacteria incorporated into a protective membrane that drugs can hardly penetrate. Secondly, MRSA bacteria can remain dormant for long periods, during which vancomycin does not work – which means that doctors need an antibiotic that can stay until the MRSA bacteria begin to wake up. .
Antibiotic Seat Tactics
The Stanford team thought the solution was not to design an antibiotic from scratch, but to modify vancomycin with r8 to help it turn into a biofilm and stay long enough to attack the cells once they wake up.
To test vancomycin with the associated r8, called V-r8, the team compared it to vancomycin against MRSA in the floating state and in biofilms. When bacteria floated freely in a liquid, vancomycin and V-r8 were able to kill most bacteria. But in biofilms, the V-r8 was about 10 times more effective, demonstrating that it could penetrate a biofilm and kill bacteria inside. The V-r8 was also hung twice as much to MRSA as to vancomycin and was much more effective at penetrating MRSA cells, suggesting that it could stay long enough to kill the cells. dormant.
These experiments, however, have all been conducted in laboratory dishes. To see how the V-r8 would face a real infection, the team treated mice infected with MRSA with V-r8 and vancomycin. They discovered that the new version had killed about 97% of bacteria after five hours, six times more effective than vancomycin without the r8 attachment.
The results do not mean that a new antibiotic goes directly to the clinic, even for tests – this is likely to happen in years. Nevertheless, he added, they suggest a new way to build antibiotics: by modifying existing antibiotics with synthetic components to give them new capabilities, such as the ability to pierce biofilms.
The team then plans to test the drug modification strategy in other bacteria in the hope of finding similar results and a way forward to fight against antibiotic resistance.
"It was only the first effort," Cegelski said.
More information:
Alexandra Antonoplis et al. An antibiotic-transporter dual function conjugate exhibits superior activity for the sterilization of MRSA biofilms and the destruction of persistent cells. Journal of the American Chemical Society (2018). DOI: 10.1021 / jacs.8b08711
With the rise in the number of drug-resistant infections and the decrease in the number of new antibiotics, the world could resort to a new strategy to fight against increasingly harsh bacteria. Stanford Chemists Report November 2 in the Newspaper Journal of the American Chemical Society a possible solution: a small molecular attachment that helps conventional antibiotics penetrate and destroy their targets.
The attachment, known as r8, helps antibiotics through the bacterium's outer defenses and encourages them to linger, said Alexandra Antonoplis, a chemistry graduate student and co-lead author with colleague Xiaoyu Zang. This penetration and toughness help kill bacteria, such as methicillin-resistant Staphylococcus aureus, or MRSA, that doctors would otherwise have trouble stopping.
Indeed, the addition of r8 to vancomycin, a frontline defense against MRSA, has made the new drug hundreds of times more effective, according to experiments conducted by Antonoplis, Zang and their advisors, Lynette Cegelski, Associate Professor of Chemistry, and Paul Wender, Professor of Chemistry Francis W. Bergstrom. The researchers believe that the same strategy could apply beyond MRSA to other drugs and infections.
"You do not have to invent a new medicine. Just fix the problems with existing drugs, "said Wender, also a member of Stanford Bio-X, Stanford Cancer Institute and Stanford ChEM-H.
The problem of MRSA
In the long run, this new approach could be good news for public health officials who have struggled to manage antibiotic-resistant infections such as MRSA. This infection, which often begins with a skin infection, accounts for more than half of hospital-acquired infections in Asia and the Americas and is the leading cause of death among antibiotic-resistant infections. .
"This is a global health problem, and we need new treatment strategies because of the growing emergence of antibiotic-resistant bacteria and the limited number of antibiotics in our pipeline," said Cegelski, also a member of Stanford Bio-X. Stanford CHEM-H. According to one report, the number of new antibiotics approved by the FDA has dropped by 90% over the last three decades. Current first-line treatment for MRSA has been used since 1958.
The antibiotic vancomycin, a first-line treatment, can prevent the spread of MRSA in some cases by preventing the construction of new bacterial cell walls, thus preventing the reproduction of the bacteria.
But vancomycin is largely useless against two of the essential defenses of the bacteria. First, MRSA tends to form biofilms, colonies of bacteria incorporated into a protective membrane that drugs can hardly penetrate. Secondly, MRSA bacteria can remain dormant for long periods, during which vancomycin does not work – which means that doctors need an antibiotic that can stay until the MRSA bacteria start to wake up.
Antibiotic Seat Tactics
The Stanford team thought the solution was not to design an antibiotic from scratch, but to modify vancomycin with r8 to help it turn into a biofilm and stay long enough to attack the cells once they wake up.
To test vancomycin with the associated r8, called V-r8, the team compared it to vancomycin against MRSA in the floating state and in biofilms. When bacteria floated freely in a liquid, vancomycin and V-r8 were able to kill most bacteria. But in biofilms, the V-r8 was about 10 times more effective, demonstrating that it could penetrate a biofilm and kill bacteria inside. The V-r8 was also hung twice as much to MRSA as to vancomycin and was much more effective at penetrating MRSA cells, suggesting that it could stay long enough to kill the cells. dormant.
These experiments, however, have all been conducted in laboratory dishes. To see how the V-r8 would face a real infection, the team treated mice infected with MRSA with V-r8 and vancomycin. They discovered that the new version had killed about 97% of bacteria after five hours, six times more effective than vancomycin without the r8 attachment.
The results do not mean that a new antibiotic goes directly to the clinic, even for tests – this is likely to happen in years. Nevertheless, he added, they suggest a new way to build antibiotics: by modifying existing antibiotics with synthetic components to give them new capabilities, such as the ability to pierce biofilms.
The team then plans to test the drug modification strategy in other bacteria in the hope of finding similar results and a way forward to fight against antibiotic resistance.
"It was only the first effort," Cegelski said.
More information:
Alexandra Antonoplis et al., A dual function antibiotic-transporter conjugate exhibits superior activity for the sterilization of MRSA biofilms and the destruction of persistent cells. Journal of the American Chemical Society (2018). DOI: 10.1021 / jacs.8b08711
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