At the Baylor College of Medicine, a research group is gaining ground in its quest for solutions to the global concern of bacterial antibiotic resistance, which was accountable for almost 1.3 million deaths in 2019.
A drug has been reported by the team in laboratory cultures and animal models considerably decreases the potential of bacteria to come up with antibiotic resistance, which may extend antibiotic effectiveness. The drug, known as dequalinium chloride (DEQ), is a proof-of-concept developed for evolution-slowing drugs.
The study has been reported in the Science Advances journal.
Most people with bacterial infections get better after completing antibiotic treatment, but there are also many cases in which people decline because the bacteria develop resistance to the antibiotic, which then can no longer kill the bacteria.”
Dr Susan M. Rosenberg, Study Corresponding Author, Baylor College of Medicine
Rosenberg is the 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. Also, she is a program leader in Baylor’s Dan L Duncan Comprehensive Cancer Center.
In this study performed, Rosenberg and her collaborators were looking for drugs that could prevent or decelerate E. coli bacteria from developing resistance to two antibiotics while being exposed to a third antibiotic, ciprofloxacin (Cipro), known to be the second most prescribed antibiotic in the U.S. and one linked to high bacterial resistance rates.
The resistance is the result of new gene mutations that take place in the bacteria during infection. The researchers observe that the drug DEQ decreases the speed at which new mutations have been developed in bacteria.
Earlier work performed from the Rosenberg laboratory had displayed that bacterial cultures in the lab exposed to cipro turn up mutation rate. They discovered a mutational “program” that has been switched on by bacterial stress responses.
Stress responses are known as genetic programs that instruct cells to increase the production of protective molecules during stress, such as stress from low concentrations of cipro. Low concentrations happen at the beginning and end of antibiotic therapies and also if doses are missed.
Also, the same stress responses increase the potential to make genetic mutations, as the Rosenberg group, then many other labs, have displayed. Few of the mutations could give resistance to cipro, while other mutations could enable resistance to antibiotics not yet faced. Mutation-generating processes that are turned on by stress responses are known as stress-induced mutation mechanisms.
Furthermore, bacteria with antibiotic-resistance mutations could sustain infection in the existence of cipro. This study is the first to display that in animal infections treated with Cipro, the bacteria trigger a known stress-induced genetic mutational process.
Cipro resistance takes place majorly by the bacteria developing new mutations, both clinically and in the laboratory, instead of obtaining genes that confer antibiotic resistance from other bacteria.
Looking for ways to avoid the development of antibiotic resistance, the scientists screened 1,120 drugs approved for human use for their potential to dial down the master bacterial stress response, which they displayed counters the advent of resistance mutations.
Besides, and counterintuitively, the researchers wished for “stealth” drugs that would not retard bacterial proliferation. This would confer a growth benefit to any bacterial mutants that withstand the mutation-slowing drug itself.
That is drugs that are not antibiotics themselves.
We found that DEQ fulfilled both requirements. Given together 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.”
Yin Zhai, Study First Author and Postdoctoral Associate, Baylor College of Medicine
Yin Zhai concludes, “In addition, we achieved this mutation-slowing effect at low DEQ concentrations, which is promising for patients. Future clinical trials are needed to evaluate the ability of DEQ to decelerate bacterial antibiotic resistance in patients.”
Zhai, Y., et al. (2023) Drugging evolution of antibiotic resistance at a regulatory network hub. Science Advances. doi.org/10.1126/sciadv.adg0188.