In their search for solutions to the global issue of bacterial antibiotic resistance, which was the cause of nearly 1.3 million deaths in 2019, a group of researchers at Baylor College of Medicine is gaining ground.
In a paper published in Science Advances, the team describes a drug that significantly reduces bacteria’s capacity to develop antibiotic resistance in animal models and laboratory cultures, potentially extending antibiotic effectiveness. Dequalinium chloride (DEQ) is a proof-of-concept drug that slows evolution.
According to Dr. Susan M. Rosenberg, who holds the Ben F. Love Chair in Cancer Research and is a Baylor professor of molecular and human genetics, biochemistry, molecular biology, molecular virology, and microbiology, “Most people with bacterial infections get better after finishing antibiotic treatment, but there are also many cases in which people decline because the bacteria develop resistance to the antibiotic, which then cannot kill the bacteria.” She also leads programs at the Dan L. Duncan Comprehensive Cancer Center (DLDCCC) at Baylor.
“Most people with bacterial infections improve after finishing antibiotic treatment, but there are many cases where people deteriorate because the bacteria develop resistance to the antibiotic, which then can no longer kill the bacteria,”
Dr. Susan M. Rosenberg, Ben F. Love Chair in Cancer Research and professor of molecular and human genetics,
Rosenberg and her colleagues looked for drugs that could slow down or prevent E. coli bacteria from becoming resistant to two antibiotics when they were exposed to a third antibiotic, ciprofloxacin (cipro), which is the second most commonly prescribed antibiotic in the United States and has been linked to high rates of bacterial resistance.
New gene mutations introduced by the bacteria during infection are the root cause of the resistance. The team discovers that the drug DEQ slows the rate at which bacteria acquire new mutations.
The rate of mutation in bacterial cultures grown in the laboratory when exposed to cipro was previously demonstrated by the Rosenberg lab. They viewed it as a mutational “program” that is turned on by bacterial pressure reactions. During times of stress, such as when cipro is present in low concentrations, stress responses are genetic programs that instruct cells to increase the production of protective molecules. When antibiotic treatments begin and end, as well as when doses are missed, low concentrations occur.
Similar pressure reactions additionally increment the capacity to make hereditary changes, as the Rosenberg bunch and, at that point, numerous different labs have shown. Some of the mutations have the potential to grant resistance to Cipro, while others have the potential to grant resistance to undiscovered antibiotics. Stress-induced mutation mechanisms are processes that initiate mutations and are activated by stress responses.
When cipro is present, bacteria that have mutated to be resistant to antibiotics can then carry on with an infection. This is the first study to demonstrate that the bacteria in cipro-treated animal infections initiate a well-known stress-induced genetic mutational process. Instead of acquiring genes that confer antibiotic resistance from other bacteria, ciprofloxacin resistance is mostly caused by the bacteria acquiring new mutations, both clinically and in the laboratory.
The researchers looked at 1,120 drugs approved for human use to see if they could reduce the master bacterial stress response, which they found prevents the emergence of resistance mutations. This was done in an effort to stop the spread of antibiotic resistance. They also wanted “stealth” drugs that wouldn’t slow bacterial proliferation, which would give any bacterial mutants that resist the mutation-slowing drug an advantage in growth. This was counterintuitive. That is, medications that do not actually contain antibiotics
We discovered that DEQ met both requirements. ” First author Yin Zhai, a postdoctoral associate in the Rosenberg lab, stated that given together with cipro, DEQ reduced the development of mutations that confer antibiotic resistance, both in laboratory cultures and animal models of infection, and bacteria did not develop resistance to DEQ. ” Furthermore, we were able to achieve this mutation-slowing effect at low DEQ concentrations, which is encouraging for patients. The efficacy of DEQ in reducing patient bacterial antibiotic resistance must be evaluated in subsequent clinical trials.”
More information: Yin Zhai et al, Drugging evolution of antibiotic resistance at a regulatory network hub, Science Advances (2023). DOI: 10.1126/sciadv.adg0188. www.science.org/doi/10.1126/sciadv.adg0188
