Antibiotic resistance is a growing global issue. According to the CDC, antibiotic resistance was associated with almost 5 million deaths in 2019. In the U.S., more than 2.8 million antimicrobial-resistant infections occur annually, killing more than 35,000 people.
Scientists looked at variants of the antibiotic albicidin to identify structural differences (colored boxes) that may be associated with reduced susceptibility to resistance. (Credit: Brady Lab)
Researchers at Rockefeller University developed a platform to identify drug resistance genes in the environment before they appear in the clinic. The platform can use this information to design resistance-evasive antibiotics. The team published their findings in PNAS.
The technology uses metagenomic surveys of the resistome, the antibiotic-resistance genes, to alert scientists to resistance mechanisms that are likely to become a problem. Using this information, scientists can optimize antibiotics for resilience against those genes.
Tomorrow’s resistance, today
In nature, bacteria have been fighting for millions of years using antibiotics and resistance genes. These same mechanisms are now appearing in clinics, making antibiotic drugs less and less effective.
In response, scientists have created more and more antibiotics every time one becomes ineffective. This system is inefficient and unsustainable, as well as unable to accurately predict resistance.
Researchers at Rockefeller University knew that resistance genes exist in the environment before they emerge in patients. “There’s now strong evidence that clinical resistance can originate among bacteria fighting in the environment,” said lead author James Peek, a research associate in the laboratory of Sean F. Brady at The Rockefeller University.
The researchers developed a way to assess the resistance genes in bacteria from soil samples and use the information to design more resilient drugs. The team focused on albicidin as a promising antibiotic candidate, building a metagenomic library of 700,000 bacterial genomes extracted from soil samples.
They exposed the bacteria to E. coli, a bacterial host that they could easily screen for resistance genes. The bacteria that survived albicidin exposure were isolated and their genomes sequenced.
Creating stronger antibiotics
The researchers sorted the resulting resistance genes into eight classes. Then they further analyzed the classes to identify how they overcame the drug. The next step was to figure out how to evade these resistance mechanisms.
The team looked at structural variants of albicidin and analyzed them for vulnerabilities against the resistant bacteria. This revealed the chemical features that enabled some antibiotic variants to remain effective while others failed to circumvent the resistance mechanisms. They found that one variant continued to function in the face of common resistance types, proving that their method could guide drug design.
By combining the most resilient variants of albicidin, scientists could create a drug that continues to work against multiple resistance mechanisms. The team hopes that pharmaceutical companies will use their method to test a potential drug’s vulnerability to resistance seen in the environment as part of the drug development process.
“It’s fast and efficient,” Peek said, “We think it would be easy for drug companies to integrate this method into the standard drug development pipeline.”
The researchers plan to apply the platform to other antibiotics developed in their lab to create drug candidates with longer clinical lifespans.
Filed Under: Omics/sequencing
