A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections-Reference-Cited by-同舟云学术

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Published:2022-09-14 Issue:662 Volume:14 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Blaskovich Mark A. T.¹^ORCID,Hansford Karl A.¹^ORCID,Butler Mark S.¹^ORCID,Ramu Soumya¹,Kavanagh Angela M.¹,Jarrad Angie M.¹^ORCID,Prasetyoputri Anggia¹^ORCID,Pitt Miranda E.¹^ORCID,Huang Johnny X.¹^ORCID,Lindahl Fredrik¹,Ziora Zyta M.¹^ORCID,Bradford Tanya¹^ORCID,Muldoon Craig¹,Rajaratnam Premraj¹^ORCID,Pelingon Ruby¹^ORCID,Edwards David J.¹,Zhang Bing¹^ORCID,Amado Maite¹,Elliott Alysha G.¹^ORCID,Zuegg Johannes¹^ORCID,Coin Lachlan¹^ORCID,Woischnig Anne-Kathrin²,Khanna Nina²^ORCID,Breidenstein Elena³,Stincone Anna³^ORCID,Mason Clive³^ORCID,Khan Nawaz³,Cho Hye-Kyung⁴^ORCID,Karau Melissa J.⁴^ORCID,Greenwood-Quaintance Kerryl E.⁴^ORCID,Patel Robin⁴⁵^ORCID,Wootton Mandy⁶^ORCID,James Meagan L.⁷^ORCID,Hutton Melanie L.⁷^ORCID,Lyras Dena⁷^ORCID,Ogunniyi Abiodun D.⁸^ORCID,Mahdi Layla K.⁸^ORCID,Trott Darren J.⁸,Wu Xiaoqian⁹,Niles Samantha⁹^ORCID,Lewis Kim⁹^ORCID,Smith Jordan R.¹⁰^ORCID,Barber Katie E.¹⁰^ORCID,Yim Juwon¹⁰,Rice Seth Alan¹⁰,Rybak Michael J.¹⁰¹¹^ORCID,Ishmael Chad R.¹²^ORCID,Hori Kellyn R.¹²^ORCID,Bernthal Nicholas M.¹²^ORCID,Francis Kevin P.¹²¹³^ORCID,Roberts Jason A.¹⁴¹⁵¹⁶,Paterson David L.¹⁴^ORCID,Cooper Matthew A.¹^ORCID

Affiliation:

1. Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.

2. University and University Hospital of Basel, Division of Infectious Diseases and Infection Biology Laboratory Department of Biomedicine, Hebelstrasse 20, CH-4031 Basel, Switzerland.

3. Summit Therapeutics, The Works, Unity Campus, Cambridgeshire, CB22 3FT, UK.

4. Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

5. Division of Public Health, Infectious Diseases and Occupational Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

6. Specialist Antimicrobial Chemotherapy Unit Public Health Wales, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, Wales.

7. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.

8. Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, South Australia 5371, Australia.

9. Antimicrobial Discovery Center, Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.

10. Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.

11. School of Medicine, Wayne State University, Detroit, MI 48201, USA.

12. Department of Orthopaedic Surgery, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.

13. PerkinElmer, 68 Elm Street, Hopkinton, MA 01748, USA.

14. University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Queensland 4029, Australia.

15. Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia.

16. Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, 30029 Nîmes, France.

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 (MIC 90 ≤ 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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