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A laboratory-based ...
A laboratory-based predictive pathway for the development of Neisseria gonorrhoeae high-level resistance to corallopyronin A, an inhibitor of bacterial RNA polymerase
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- Balthazar, Jacqueline T. (författare)
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
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- Golparian, Daniel, 1984- (författare)
- Örebro universitet,Institutionen för medicinska vetenskaper,WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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- Unemo, Magnus, 1970- (författare)
- Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Institute for Global Health, University College London, London, United Kingdom
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- Read, Timothy D. (författare)
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA; Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, Georgia, USA
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- Grosse, Miriam (författare)
- Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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- Stadler, Marc (författare)
- Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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- Pfarr, Kenneth (författare)
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany
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- Schiefer, Andrea (författare)
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany
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- Hoerauf, Achim (författare)
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany
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- Edwards, Jennifer L. (författare)
- The Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA
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- Vassylyev, Dmitry G. (författare)
- Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama-Birmingham, Birmingham, Alabama, USA
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- Shafer, William M. (författare)
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA; Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, Georgia, USA; Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center (Atlanta), Decatur, Georgia, USA
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(creator_code:org_t)
- American Society for Microbiology, 2024
- 2024
- Engelska.
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Ingår i: Microbiology Spectrum. - : American Society for Microbiology. - 2165-0497. ; 12:6
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The continued emergence of Neisseria gonorrhoeae strains that express resistance to multiple antibiotics, including the last drug for empiric monotherapy (ceftriaxone), necessitates the development of new treatment options to cure gonorrheal infections. Toward this goal, we recently reported that corallopyronin A (CorA), which targets the switch region of the β' subunit (RpoC) of bacterial DNA-dependent RNA polymerase (RNAP), has potent anti-gonococcal activity against a panel of multidrug-resistant clinical strains. Moreover, in that study, CorA could eliminate gonococcal infection of primary human epithelial cells and gonococci in a biofilm state. To determine if N. gonorrhoeae could develop high-level resistance to CorA in a single step, we sought to isolate spontaneous mutants expressing any CorA resistance phenotypes. However, no single-step mutants with high-level CorA resistance were isolated. High-level CorA resistance could only be achieved in this study through a multi-step pathway involving over-expression of the MtrCDE drug efflux pump and single amino acid changes in the β and β' subunits (RpoB and RpoC, respectively) of RNAP. Molecular modeling of RpoB and RpoC interacting with CorA was used to deduce how the amino acid changes in RpoB and RpoC could influence gonococcal resistance to CorA. Bioinformatic analyses of whole genome sequences of clinical gonococcal isolates indicated that the CorA resistance determining mutations in RpoB/C, identified herein, are very rare (≤ 0.0029%), suggesting that the proposed pathway for resistance is predictive of how this phenotype could potentially evolve if CorA is used therapeutically to treat gonorrhea in the future. IMPORTANCE: The continued emergence of multi-antibiotic-resistant strains of Neisseria gonorrhoeae necessitates the development of new antibiotics that are effective against this human pathogen. We previously described that the RNA polymerase-targeting antibiotic corallopyronin A (CorA) has potent activity against a large collection of clinical strains that express different antibiotic resistance phenotypes including when such gonococci are in a biofilm state. Herein, we tested whether a CorA-sensitive gonococcal strain could develop spontaneous resistance. Our finding that CorA resistance could only be achieved by a multi-step process involving over-expression of the MtrCDE efflux pump and single amino acid changes in RpoB and RpoC suggests that such resistance may be difficult for gonococci to evolve if this antibiotic is used in the future to treat gonorrheal infections that are refractory to cure by other antibiotics.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Nyckelord
- Neisseria gonorrhoeae
- RNAP
- RpoB/RpoC
- corallopyronin A
- resistance
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Balthazar, Jacqu ...
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Golparian, Danie ...
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Unemo, Magnus, 1 ...
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Read, Timothy D.
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Grosse, Miriam
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Stadler, Marc
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Pfarr, Kenneth
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Schiefer, Andrea
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Hoerauf, Achim
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Edwards, Jennife ...
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Vassylyev, Dmitr ...
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Shafer, William ...
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Örebro universitet