TSUKUBA, JAPAN — Antibiotic resistance (ARE) is a threat to human health worldwide, as diverse proteins allow pathogenic bacteria to develop increasing levels of resistance to antibiotic medicines. Now, a team from the University of Tsukuba, Japan, has discovered the characteristics of certain proteins known as ATP-binding cassette proteins of the F subfamily (ABCFs) from three different bacteria, providing insights into their function and role that, with other resistance mechanisms, convey powerful cumulative resistance.
Antibiotics often target the bacterial ribosome, the machinery within a cell that produces proteins. Bacteria, therefore, develop ways to protect the ribosome as ways to resist antibiotics. The ARE-ABCFs are associated with ribosomal antibiotic resistance in various bacteria. The expression of the ARE-ABCFs is induced by an antibiotic challenge—when the bacteria encounter an antibiotic and the ribosome "stalls" the process of translation that makes proteins, the ARE-ABCFs are activated and the resistance mechanisms kick in to protect the bacteria.
Multiple mechanisms synergistically convey antibiotic resistance to C. difficile
The class of bacteria, Clostridia, contains some important human pathogens, such as Clostridium perfringens which causes food poisoning, and Clostridioides difficile which has a high level of antibiotic resistance and can cause chronic infections, diarrhea, and dangerous nosocomial infections.
"The risk of infection with C. difficile is known to increase after treatment with an antibiotic called clindamycin, but the reason for this was unknown," says lead author Nozomu Obana, PhD, assistant professor at the University of Tsukuba. "Our research showed that the ARE-ABCF found in Clostridia bacteria, called Clostridial pleuromutilin and lincosamide resistance protein (CplR), conveys resistance to the class of antibiotics to which clindamycin belongs."
The research team also showed that CplR may work in synergy with another method of antibiotic resistance mediated by an enzyme, erythromycin resistance methylase (Erm). Erm adds a methyl group onto the ribosomal RNA, the primary component of the ribosome. This methylation conveys resistance to other classes of antibiotics.
"These two mechanisms working in synergy results in extremely high levels of antibiotic resistance, even to a synthetic antibiotic that is usually effective against resistant bacteria," explains Obana. This may be why treatment with clindamycin, inducing expression of CplR, can lead to an increased risk of C. difficile infection.
This study provides insights into resistance mechanisms in human pathogens that have direct clinical importance. These findings will help develop new antibiotics that override or impede bacterial ribosome protection in novel ways and that do not induce the expression of ARE-ABCFs.
- This press release is supported by the University of Tsukuba