Researchers from Baylor College of Medicine have been scrutinizing the mechanism that fuels antibiotic resistance at the molecular level to help solve this rising issue.
Scientists, through their study published in the journal Molecular Cell, confirm important and unexpected initial steps that support resistance to ciprofloxacin. These results may make is possible to postpone the emergence of bacterial resistance, thereby preserving the efficacy of both new and existing antibiotics.
Cipro fragments the DNA molecule that collects inside bacteria. Accordingly, a DNA damage response starts to repair the breaks. In this study, the researchers uncovered the molecular mechanisms of the first steps between the antibiotic causing DNA breaks and the bacteria inducing the DNA damage response. The researchers learned the steps involved in stress-induced mutagenesis and found two stress responses, the general stress response and the DNA damage response, to be essential.
Dr. Yin Zhai, the study's author, said, "surprisingly, we found an unexpected molecule involved in modulating DNA repair. Normally, cells regulate their movements by producing specific proteins that mediate the desired function. However, in this case, the initial step to activate the DNA repair response was not about activating certain genes that produce certain proteins."
Rather, the first step was disrupting the activity of a protein already present, RNA polymerase, which is crucial for protein synthesis.
Zhai said, "Our study found that DNA restoration is regulated by RNA polymerase. Furthermore, a nucleotide ppGpp, present in bacteria when exposed to a stressful environment like ciprofloxacin, hooks to RNA polymerase via two sites crucial for turning on the repair and general stress responses. Bugging into one of these sites stops DNA repair, especially at the DNA sequences populated by RNA polymerase."
Dr. Christophe Herman, professor of molecular and human genetics, molecular virology, and microbiology and the study's co-corresponding author, said, "ppGpp hooks to DNA-bound RNA polymerase, directing it to stop and backtrack along the DNA to restore it."
Furthermore, ciprofloxacin has an action similar to the anti-cancer drug etoposide, which damages human DNA in tumors. These findings unfurl new possibilities to design methods that would meddle with the development of antibiotic resistance and help turn the tide on this global health peril and may also generate additional new strategies to fight cancer chemotherapy resistance.
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