Study reports drug that dramatically reduces bacteria’s ability to develop antibiotic resistance

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A team of researchers from Baylor College of Medicine are gaining momentum in their search for solutions to the global problem of bacterial resistance to antibiotics, responsible for nearly 1.3 million deaths in 2019.

The team reports in the newspaper Scientists progress a drug that, in laboratory cultures and animal models, significantly reduces the ability of bacteria to develop resistance to antibiotics, which could prolong the effectiveness of antibiotics. The drug, called dequalinium chloride (DEQ), is a proof-of-concept for evolution-slowing drugs.

“Most people with bacterial infections get better after completing antibiotic treatment, but there are also many cases where people decline because the bacteria develop resistance to the antibiotic, which then can no longer kill. bacteria,” said corresponding author Dr. Susan M. Rosenberg, Ben F. Love Chair in Cancer Research and Professor of Molecular and Human Genetics, Biochemistry and Molecular Biology and Molecular Virology and Microbiology at Baylor. She is also Program Manager at Baylor’s Dan L Duncan Comprehensive Cancer Center (DLDCCC).

In this study, Rosenberg and his colleagues searched for drugs that could prevent or slow the development of resistance in E. coli bacteria to two antibiotics when exposed to a third antibiotic, ciprofloxacin (cipro), the second most common antibiotic. most prescribed in the United States and an associate. with high bacterial resistance rates.

Resistance is caused by new genetic mutations that occur in bacteria upon infection. The drug DEQ reduces the rate at which new mutations form in bacteria, the team finds.

Previous work from Rosenberg’s lab had shown that bacterial cultures in the lab exposed to cipro increased the mutation rate. They found a mutational “program” that is activated by bacterial responses to stress. Stress responses are genetic programs that instruct cells to increase the production of protective molecules during stress, including stress from low cipro concentrations. Low levels occur at the start and end of antibiotic treatments and if doses are missed.

The same stress responses also increase the ability to make genetic mutations, the Rosenberg group showed, and then many other labs. Some of the mutations may confer resistance to cipro, while other mutations may allow resistance to previously unmet antibiotics. Mutation-generating processes activated by stress responses are called stress-induced mutation mechanisms.

Bacteria with antibiotic resistance mutations can then sustain an infection in the presence of cipro. This study is the first to show that in animal infections treated with cipro, the bacterium activates a genetic mutational process induced by stress. Resistance to Cipro occurs primarily by bacteria developing new mutations, both clinically and in the laboratory, rather than by acquiring genes that confer resistance to antibiotics from other bacteria.

Seeking to prevent the development of antibiotic resistance, the researchers screened 1,120 drugs approved for human use for their ability to reduce the key bacterial stress response, which they believe thwarts the emergence of resistance mutations. . Additionally, and against all odds, they wanted “stealth” drugs that would not slow bacterial proliferation, thereby conferring a growth advantage on any bacterial mutants that are resistant to the mutation-slowing drug itself. That is, drugs that are not themselves antibiotics.

“We found that DEQ met both conditions. Given with cipro, DEQ reduced the development of mutations that confer antibiotic resistance, both in laboratory cultures and in animal models of infection, and bacteria did not develop resistance to DEQ,” said first author Yin Zhai, postdoctoral associate at the Rosenberg lab. “Furthermore, we achieved this mutation-slowing effect at low DEQ concentrations, which is promising for patients. Future clinical trials are needed to assess the ability of DEQ to slow bacterial resistance to antibiotics in patients.

More information:
Yin Zhai et al, Evolution of antibiotic resistance medication in a regulatory network center, Scientists progress (2023). DOI: 10.1126/sciadv.adg0188.

Journal information:
Scientists progress

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