Predicting the Unpredictable: New Tool Tackles Antibiotic Resistance

Multidrug-resistant bacteria claim around five million lives annually, with new resistant strains emerging at a pace that outstrips the development of effective treatments. However, researchers have made a breakthrough with a novel platform that detects drug resistance genes in the environment before they appear in clinical settings. This platform uses metagenomic analysis of the "resistome" as an early warning system, enabling scientists to anticipate potential resistance issues (1^✔ ✔Trusted Source
Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace

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Antibiotics: A Constant Chase

Antibiotic development is often an endless cycle of finding new compounds to replace those that have become ineffective. Although scientists try to optimize drugs against resistances predicted in the lab—and resistant strains that crop up in the clinic—the current system has proven ill-equipped to accurately anticipate novel threats.

Brady’s Laboratory of Genetically Encoded Small Molecules at Rockefeller suspected that there was a better way forward. They knew that bacteria in nature have spent millennia battling one another with antibiotics and resistance genes, forming a vast reservoir of resistance mechanisms in the environment, which we now know includes many of the same mechanisms that appeared in clinics. For instance, the very same types of resistance genes that dealt a major blow to antibiotic classes such as beta-lactams circulated in populations of soil bacteria long before these drugs entered clinical use.

“There’s now strong evidence that clinical resistance can originate among bacteria fighting in the environment,” Peek says. Tomorrow’s resistance mechanisms may already be present in today’s soil samples. The challenge was finding a way to access that information and use it to improve human health.

Albicidin: A New Hope in the Fight Against Antibiotic Resistance

For the study, the team focused on albicidin, a promising antibiotic candidate. With 3.5 terabase pairs of microbial DNA extracted from soil—roughly 700,000 bacterial genomes—they built a metagenomic library and introduced it into E. Coli, a model bacterial host that could be easily screened to identify albicidin resistance genes. Bacteria that survived albicidin exposure were isolated, and their resistance genes were sequenced. The screen revealed eight classes of resistance genes, which were further analyzed to identify how each disables the drug.

To figure out how to evade these resistance mechanisms, the researchers looked at natural structural variants of albicidin with the rationale that these variants may have evolved in the battle between soil microbes to circumvent resistance. Each variant tested had a unique vulnerability profile against the different types of resistance, which revealed chemical features that helped some variants remain effective. With this information, they began prioritizing promising drug leads. One variant (congener 10), with several structural differences compared to albicidin, was particularly promising as it continued to function in the face of the most common resistance types.

Ultimately, the team demonstrated that their method could guide drug design by engineering new versions of albicidin that combined the most protective features into compounds that remained potent in the face of even the most formidable resistance proteins.

Brady, Peek, and colleagues hope that pharmaceutical companies will adopt their technique to test a candidate drug’s susceptibility to pre-existing forms of resistance in the environment as they decide whether to move forward with development. “It’s fast and efficient,” Peek says. “We think it would be easy for drug companies to integrate this method into the standard drug development pipeline.”

Reducing Resistance Risk in Antibiotic Development

In the short term, the team plans to apply their screening platform to other antibiotics developed in the Brady lab. By identifying and addressing environmental vulnerabilities early on, they hope to generate candidates with longer clinical lifespans and fewer chances of being undermined by resistance. It holds real promise for increasing the likelihood that new antibiotics will avoid rapid resistance upon entering the clinic.

Reference:

1. The challenges and some emerging strategies for tackling a global menace - (https://pmc.ncbi.nlm.nih.gov/articles/PMC9459344/)

Source-Eurekalert