Your browser doesn't support javascript.
loading
A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.
Blaskovich, Mark A T; Hansford, Karl A; Butler, Mark S; Ramu, Soumya; Kavanagh, Angela M; Jarrad, Angie M; Prasetyoputri, Anggia; Pitt, Miranda E; Huang, Johnny X; Lindahl, Fredrik; Ziora, Zyta M; Bradford, Tanya; Muldoon, Craig; Rajaratnam, Premraj; Pelingon, Ruby; Edwards, David J; Zhang, Bing; Amado, Maite; Elliott, Alysha G; Zuegg, Johannes; Coin, Lachlan; Woischnig, Anne-Kathrin; Khanna, Nina; Breidenstein, Elena; Stincone, Anna; Mason, Clive; Khan, Nawaz; Cho, Hye-Kyung; Karau, Melissa J; Greenwood-Quaintance, Kerryl E; Patel, Robin; Wootton, Mandy; James, Meagan L; Hutton, Melanie L; Lyras, Dena; Ogunniyi, Abiodun D; Mahdi, Layla K; Trott, Darren J; Wu, Xiaoqian; Niles, Samantha; Lewis, Kim; Smith, Jordan R; Barber, Katie E; Yim, Juwon; Rice, Seth Alan; Rybak, Michael J; Ishmael, Chad R; Hori, Kellyn R; Bernthal, Nicholas M; Francis, Kevin P.
Affiliation
  • Blaskovich MAT; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Hansford KA; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Butler MS; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Ramu S; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Kavanagh AM; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Jarrad AM; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Prasetyoputri A; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Pitt ME; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Huang JX; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Lindahl F; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Ziora ZM; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Bradford T; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Muldoon C; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Rajaratnam P; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Pelingon R; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Edwards DJ; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Zhang B; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Amado M; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Elliott AG; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Zuegg J; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Coin L; Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
  • Woischnig AK; University and University Hospital of Basel, Division of Infectious Diseases and Infection Biology Laboratory Department of Biomedicine, Hebelstrasse 20, CH-4031 Basel, Switzerland.
  • Khanna N; University and University Hospital of Basel, Division of Infectious Diseases and Infection Biology Laboratory Department of Biomedicine, Hebelstrasse 20, CH-4031 Basel, Switzerland.
  • Breidenstein E; Summit Therapeutics, The Works, Unity Campus, Cambridgeshire, CB22 3FT, UK.
  • Stincone A; Summit Therapeutics, The Works, Unity Campus, Cambridgeshire, CB22 3FT, UK.
  • Mason C; Summit Therapeutics, The Works, Unity Campus, Cambridgeshire, CB22 3FT, UK.
  • Khan N; Summit Therapeutics, The Works, Unity Campus, Cambridgeshire, CB22 3FT, UK.
  • Cho HK; Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Karau MJ; Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Greenwood-Quaintance KE; Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Patel R; Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Wootton M; Division of Public Health, Infectious Diseases and Occupational Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • James ML; Specialist Antimicrobial Chemotherapy Unit Public Health Wales, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, Wales.
  • Hutton ML; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
  • Lyras D; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
  • Ogunniyi AD; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
  • Mahdi LK; Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, South Australia 5371, Australia.
  • Trott DJ; Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, South Australia 5371, Australia.
  • Wu X; Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, South Australia 5371, Australia.
  • Niles S; Antimicrobial Discovery Center, Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
  • Lewis K; Antimicrobial Discovery Center, Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
  • Smith JR; Antimicrobial Discovery Center, Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
  • Barber KE; Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • Yim J; Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • Rice SA; Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • Rybak MJ; Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • Ishmael CR; Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • Hori KR; School of Medicine, Wayne State University, Detroit, MI 48201, USA.
  • Bernthal NM; Department of Orthopaedic Surgery, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
  • Francis KP; Department of Orthopaedic Surgery, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Sci Transl Med ; 14(662): eabj2381, 2022 09 14.
Article in En | MEDLINE | ID: mdl-36103517
ABSTRACT
Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.
Subject(s)
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gram-Positive Bacterial Infections / Methicillin-Resistant Staphylococcus aureus / Anti-Infective Agents Limits: Animals Language: En Journal: Sci Transl Med Journal subject: CIENCIA / MEDICINA Year: 2022 Document type: Article Affiliation country:
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gram-Positive Bacterial Infections / Methicillin-Resistant Staphylococcus aureus / Anti-Infective Agents Limits: Animals Language: En Journal: Sci Transl Med Journal subject: CIENCIA / MEDICINA Year: 2022 Document type: Article Affiliation country: