Antibiotic resistance is a global health threat causing concern among scientists and healthcare professionals worldwide. In 2019 alone, an estimated 1.3 million deaths were attributed to antibiotic-resistant bacterial infections. However, researchers at Baylor College of Medicine have made strides against this problem by studying the process driving antibiotic resistance at the molecular level.
In a recent study published in Molecular Cell, the research team discovered crucial and surprising first steps that promote resistance to ciprofloxacin, or cipro for short, which is one of the most commonly prescribed antibiotics. The study revealed 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.
These stress responses promote mutations, generating mutant bacteria that are resistant to cipro. Once these cipro-resistant mutants emerge, they continue to grow and sustain an infection that can no longer be eliminated with cipro.
The team found that cipro induces breaks in DNA, which accumulate inside bacteria and consequently trigger a DNA damage response to repair the damage. They discovered that two stress responses, the general stress response and the DNA-damage response, are essential for increasing mutagenesis. Furthermore, the scientists uncovered the molecular mechanisms of the first steps between the antibiotic causing DNA breaks and the bacteria turning on the DNA damage response.
One of the most surprising findings was the involvement of a small molecule called nucleotide ppGpp. This molecule, which is present in bacteria exposed to a stressful environment, binds to and interferes with RNA polymerase sites, causing ppGpp to turn off DNA repair at these specific sites.
The researchers believe that these findings provide new opportunities to design strategies that would interfere with the development of antibiotic resistance and help turn the tide on this global health threat. Moreover, since cipro breaks bacterial DNA similarly to how the anti-cancer drug etoposide breaks human DNA in tumors, the research may also lead to new tools to combat cancer chemotherapy resistance.
The Baylor College of Medicine team sheds new light on the process that drives antibiotic resistance at the molecular level. It highlights the crucial and surprising first steps that promote resistance to cipro, one of the most commonly prescribed antibiotics, and points at potential strategies to prevent bacteria from developing resistance. The findings provide hope for new approaches to combat antibiotic resistance, one of humanity's most significant global health threats.