Author information

¹Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

²Department of Infectious Diseases, Monash Health, Clayton, Victoria, Australia.

³Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

⁴School of Chemistry and Molecular Biosciences, The University of Queensland, Saint Lucia Campus, Saint Lucia, Queensland, Australia.

⁵Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

⁶Department of Infectious Diseases & Immunology, Austin Health, Melbourne, Victoria, Australia.

⁷Centre for Pathogen Genomics, The University of Melbourne, Melbourne, Victoria, Australia.

⁸School of Chemistry, The University of Melbourne, Melbourne, Victoria, Australia.

⁹Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia.

¹⁰Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.

¹¹Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.

¹²Molecular Sciences and Technology, College of Science and Engineering, Flinders University, Adelaide, South Australia, Australia.

¹³Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

¹⁴Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.

¹⁵Institute of Clinical Microbiology and Hygiene, University Medical Center, Regensburg, Germany.

¹⁶Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center, Regensburg, Germany.

¹⁷DEMI Unit, Department of Computational Biology, Institut Pasteur, Paris, France.

¹⁸Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. bhowden@unimelb.edu.au.

¹⁹Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. bhowden@unimelb.edu.au.

²⁰Department of Infectious Diseases & Immunology, Austin Health, Melbourne, Victoria, Australia. bhowden@unimelb.edu.au.

²¹Centre for Pathogen Genomics, The University of Melbourne, Melbourne, Victoria, Australia. bhowden@unimelb.edu.au.

²²Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. glen.carter@unimelb.edu.au.

²³Centre for Pathogen Genomics, The University of Melbourne, Melbourne, Victoria, Australia. glen.carter@unimelb.edu.au.

Abstract

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health¹. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action², but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease³, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered 'low risk' for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.