Newswise — Tsukuba, Japan—Antibiotic resistance (ARE) poses a global peril to human well-being, as various proteins enable pathogenic bacteria to cultivate heightened resistance against antibiotic medications. Presently, researchers at the University of Tsukuba have unraveled the attributes of specific proteins dubbed ARE-ABCFs, originating from three distinct bacteria. This revelation sheds light on their function and significance, which, when combined with other resistance mechanisms, bestow an exceptionally potent collective resistance.
Antibiotics frequently aim at the bacterial ribosome, the cellular apparatus responsible for protein synthesis. Consequently, bacteria devise strategies to shield the ribosome in order to resist antibiotics. The ARE-ABCF proteins are linked to ribosomal antibiotic resistance across different bacterial species. These proteins are triggered by an antibiotic assault, wherein the ribosome halts the protein translation process. Subsequently, the activation of ARE-ABCFs initiates the defense mechanisms, fortifying the bacteria against the antibiotic's effects.
Within the bacterial realm, a group known as "Clostridia" encompasses several significant human pathogens. Notably, Clostridium perfringens is responsible for food poisoning, while Clostridioides difficile exhibits formidable antibiotic resistance and can lead to persistent infections, diarrhea, and perilous "nosocomial" infections. These nosocomial infections are acquired by patients subsequent to their admission to hospitals or other healthcare facilities.
"The susceptibility to C. difficile infection was observed to rise following the administration of clindamycin, an antibiotic, but the underlying cause remained elusive," stated Assistant Professor Nozomu Obana, the lead author. "Our investigation revealed that the ARE-ABCF protein, known as CplR, present in Clostridia bacteria, imparts resistance specifically to the class of antibiotics that includes clindamycin."
Furthermore, the research team demonstrated that CplR can synergistically cooperate with another mechanism of antibiotic resistance facilitated by a protein named "Erm." Erm performs the addition of a methyl group to the ribosomal RNA, which is a vital constituent of the ribosome. This methylation process imparts resistance to distinct classes of antibiotics.
"The collaborative action of these two mechanisms leads to remarkably elevated levels of antibiotic resistance, surpassing even the efficacy of synthetic antibiotics designed to combat resistant bacteria," elucidated Professor Obana, the lead author. This elucidation offers a rationale for why treatment involving clindamycin, which induces the expression of CplR, can escalate the vulnerability to C. difficile infection.
This study offers valuable insights into the resistance mechanisms employed by human pathogens, holding significant clinical implications. These findings will contribute to the development of new antibiotics that can target the ribosome using innovative approaches, circumventing the induction of ARE-ABCF resistance proteins. Such advancements aim to provide alternative strategies to inhibit the ribosome effectively and combat antibiotic resistance in pathogens.
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (grant WI3285/8-1 to D.N.W), Swedish Research Council (Vetenskapsrådet) grants (2019-01085 to G.C.A., 2017- 03783 and 2021-01146 to V.H.), Cancerfonden (20 0872 Pj to V.H.), the Estonian Research Council (PRG335 to V.H.), the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health (R01AI168228 to A.G.M.) and the European Union from the European Regional Development Fund through the Centre of Excellence in Molecular Cell Engineering (2014-2020.4.01.15-0013 to V.H.). V.H. and D.N.W. groups are also supported by the Swedish Research Council (2018-00956 to V.H.) and the Deutsche Zentrum für Luft- und Raumfahrt (DLR01Kl1820 to D.N.W.) within the RIBOTARGET consortium under the framework of JPIAMR. G.C.A. and V.H. were also supported by a project grant from the Knut and Alice Wallenberg Foundation (2020-0037 to G.C.A.). H.T. was supported by JST, ACT X, Japan grant 26 JP1159335. N.O. was supported by JSPS KAKENHI Grant Number 21K07018. K.J.Y.W. was supported by a National Science Scholarship (PhD) by the Agency for Science, Technology and Research, Singapore.
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