Study explores the mechanism that fuels antibiotic resistance

Antibiotic resistance is a growing global health concern. Antibiotic-resistant bacterial infections reportedly caused an estimated 1.3 million deaths globally in 2019 alone. Researchers at the Baylor College of Medicine have been examining the mechanism that fuels antibiotic resistance at the molecular level to help find a solution.
They document important and unexpected initial steps that support resistance to ciprofloxacin, also known as cipro, one of the most frequently given antibiotics, in the journal Molecular Cell. Co-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, said, “Previous work in our lab has shown that when bacteria are exposed to a stressful environment, such as the presence of cipro, they initiate a series of responses to attempt to survive the toxic effect of the antibiotic.”
Rosenberg, also program leader in Baylor’s Dan L Duncan Comprehensive Cancer Centre (DLDCCC), said, “We discovered that cipro triggers cellular stress responses that promote mutations. This phenomenon, known as stress-induced mutagenesis, generates mutant bacteria, some of which are resistant to cipro. Cipro-resistant mutants keep on growing, sustaining an infection that can no longer be eliminated with cipro.”
Cipro induces breaks in the DNA molecule, accumulating inside bacteria and consequently triggering a DNA damage response to repair the breaks. The lab’s discoveries of the steps involved in stress-induced mutagenesis revealed that two stress responses are essential - the general stress response and the DNA-damage response.
First author Dr. Yin Zhai, a postdoctoral associate in the Rosenberg lab, said, “We were surprised to find an unexpected molecule involved in modulating DNA repair. Usually, cells regulate their activities by producing specific proteins that mediate the desired function. But in this case, the first step to turn on the DNA repair response was not about activating certain genes that produce certain proteins.”
They said, “We discovered that RNA polymerase also plays a major role in regulating DNA repair. A small molecule called nucleotide ppGpp, which is present in bacteria exposed to a stressful environment, binds to RNA polymerase through two separate sites that are essential for turning on the repair response and the general stress response. Interfering with one of these sites turn off DNA repair specifically at the DNA sequences occupied by RNA polymerase.”
"We are excited about these findings," Rosenberg said. "They open new opportunities to design strategies that would interfere with the development of antibiotic resistance and help turn the tide on this global health threat. Also, cipro breaks bacterial DNA in the same way that the anti-cancer drug etoposide breaks human DNA in tumours. We hope this may additionally lead to new tools to combat cancer chemotherapy resistance.”