University of South Florida

Antibiotics intended to heal can actually encourage resistance of life-threatening C. difficile infection

USF research teams led by Dr. Yu Chen and Dr. Xingmin Sun describe ways to control the No. 1 hospital-acquired bacterial infection in a paper published in the journal Nature Communications.

The ironic joke goes that if you want to get sick, stay in a hospital. That’s because hospitals can harbor germs that take advantage of a patient’s weakened state, complicating the illness that brought them there in the first place.

But health officials have an arsenal to keep people safe, including cephalosporins, strong antibiotics that fight bacteria such as staphylococcus and streptococcus. Cephalosporins are often used against skin, soft tissue and surgery related infections.

Dr. Yu Chen

However, treatment with β-lactam antibiotics – particularly cephalosporins – is a major risk factor for the virulent Clostridioides difficile infection (CDI), which attacks the large intestine and can cause diarrhea and life-threatening colitis.

These complications are explained in a recent paper published in the journal Nature Communications by teams that includes senior author Dr. Yu Chen, professor in the Department of Molecular Medicine in the USF Health Morsani College of Medicine, and co-corresponding author Dr. Xingmin Sun, associate professor in the Department of Molecular Medicine in the Morsani College of Medicine. Several other USF research teams, led by Rays Jiang, PhD, Prahathees Eswara, PhD, and Ioannis Gelis, PhD, also contributed to the study.

“When you give a person an antibiotic to treat a disease, one of the consequences is the antibiotic can wipe out a lot of the good bacteria in the gut,’’ Dr. Chen said. “But in this case, C. difficile is resistant to cephalosporins, so it creates a high-risk factor. And if people are under prolonged antibiotic treatment, they are at an even higher risk for CDI.’’

Cephalosporin resistance in CDI is well documented, but the underlying mechanism has, until this point, remained unclear. The USF Health team used a combination of experimental techniques to characterize the molecular basis of cephalosporin resistance in CDI, which is the No. 1 hospital-acquired bacterial infection in the United States, according to the Centers for Disease Control and Prevention.

Initially, antibiotics are administered for an unrelated infection or prophylaxis, causing the gut flora diversity to diminish. Without competition from the good bacteria in the large intestine, CDI can easily proliferate, secreting toxins that cause cell death.

“The primary risk factor for CDI are broad-spectrum antibiotics, specifically those with weak activity against C. difficile and strong activity against other gut bacteria,’’ the authors state.

These broad-spectrum antibiotics irreversibly inhibit a bacterium’s penicillin-binding proteins (PBPs), which are enzymes that assemble in the bacterial cell wall. These proteins are critical not only for the growth of C. difficile, but also to produce its spores, which are resistant to harsh environmental conditions and contribute to the high recurrent rates of CDI. The challenge for researchers is that, prior to the Nature Communications report, there was little information about the PBPs of C. difficile.

As a common hospital-acquired infection, the pathogenesis of CDI is well-understood. It causes about 500,000 infections each year in the United States, and one in about 10 people over 65 with the infection die within a month, according to the CDC.

“We want to know more about C. difficile resistance so it (data) can be used to create new therapies for the future,’’ Chen said. “This research will help us understand more about certain drugs that are risks factors for infection.’’

The researchers emphasized two key findings in the journal report. First, by elucidating the three-dimensional structures of key PBPs from C. difficile and how they interact with beta-lactam antibiotics, the USF Health teams showed that cephalosporins do not have strong inhibitory activity against the PBPs essential for C. difficile growth and are thus unable to kill the bacterium.

Second, they also found that many of these proteins require zinc to be functional, partly explaining why dietary zinc is also a risk factor for CDI. Furthermore, the results can be used to develop new inhibitors of these PBPs to kill C. difficile and eliminate its spores. Such compounds can be developed into new antibiotics to treat CDI.

CDI can affect anyone, and symptoms often are painful and life threatening. Risk factors include:

  • Being 65 or older
  • Recent stay at a hospital or nursing home
  • A weakened immune system, such as people with HIV/AIDS, cancer, or organ transplant patients taking immunosuppressive drugs
  • Previous infection with CDI or known exposure to the germs

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The journal Nature Communications is an open access, multidisciplinary journal dedicated to publishing high-quality research in all areas of the biological, health, physical, chemical and Earth sciences. Papers published by the journal aim to represent important advances of significance to specialists within each field.

Story by Kurt Loft


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