The drug helps reduce bacterial resistance to antibiotics

A team of researchers from Baylor College of Medicine in the United States are gaining momentum in their search for solutions to the global problem of bacterial resistance to antibioticsresponsible for almost 1.3 million deaths in 2019.

The team reports in the newspaper Scientists progress a drug which, in laboratory cultures and animal modelsdrastically reduces the ability to bacteria develop antibiotic resistance, which could prolong the effectiveness of antibiotics. The drug, called dequalinium chloride (QED), 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, Professor of Molecular and Genetics, Biochemistry and Molecular Biology and Molecular Virology and Microbiology at Baylor.

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

Resistance is caused by new genetic mutations that occur in bacteria upon infection. Drugs QED reduces the rate at which new mutations form in bacteria, according to the team.

Previous work from Rosenberg’s laboratory had shown that bacterial cultures in the laboratory exposed to cipro increase 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 due to low concentrations of cipro. 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 mutations can confer resistance to cipro, while other mutations may allow for previously unencountered antibiotic resistance. 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 ciprobacteria activate a known stress-induced genetic mutation process. Cipro resistance 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 down bacterial proliferation, which would confer 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 QED meets both requirements. given with cipro, QED reduced the development of mutations that confer resistance to antibiotics, both in laboratory cultures and in animal models of infection, and bacteria did not develop resistance to QEDconcluded first author Yin Zhai, a postdoctoral associate at the Rosenberg lab. “Additionally, we got this mutation-slowing effect at low QED concentrations, which is promising for patients. Future clinical trials are needed to assess the ability of QED to slow bacterial resistance to antibiotics in patients.