Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent
ABSTRACT Multidrug-resistant (MDR) Acinetobacter spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C Acinetobacter-derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-la...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00159-19 |
| _version_ | 1818346731341873152 |
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| author | Melissa D. Barnes Vijay Kumar Christopher R. Bethel Samir H. Moussa John O’Donnell Joseph D. Rutter Caryn E. Good Kristine M. Hujer Andrea M. Hujer Steve H. Marshall Barry N. Kreiswirth Sandra S. Richter Philip N. Rather Michael R. Jacobs Krisztina M. Papp-Wallace Focco van den Akker Robert A. Bonomo |
| author_facet | Melissa D. Barnes Vijay Kumar Christopher R. Bethel Samir H. Moussa John O’Donnell Joseph D. Rutter Caryn E. Good Kristine M. Hujer Andrea M. Hujer Steve H. Marshall Barry N. Kreiswirth Sandra S. Richter Philip N. Rather Michael R. Jacobs Krisztina M. Papp-Wallace Focco van den Akker Robert A. Bonomo |
| author_sort | Melissa D. Barnes |
| collection | DOAJ |
| description | ABSTRACT Multidrug-resistant (MDR) Acinetobacter spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C Acinetobacter-derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-lactamases. Importantly, OXA-like β-lactamases represent a gap in the spectrum of inhibition by recently approved β-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D β-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical Acinetobacter baumannii isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in A. baumannii. The combination of sulbactam and ETX2514 was efficacious against A. baumannii carrying blaTEM-1, blaADC-82, blaOXA-23, and blaOXA-66 in a neutropenic murine thigh infection model. We also show that, in vitro, ETX2514 inhibited ADC-7 (k2/Ki 1.0 ± 0.1 × 106 M−1 s−1) and OXA-58 (k2/Ki 2.5 ± 0.3 × 105 M−1 s−1). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D β-lactamases as well as class A and C β-lactamases and is a promising therapeutic candidate for infections caused by MDR Acinetobacter spp. IMPORTANCE The number and diversity of β-lactamases are steadily increasing. The emergence of β-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover β-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for Acinetobacter spp. producing class D β-lactamases. |
| first_indexed | 2024-12-13T17:22:55Z |
| format | Article |
| id | doaj.art-e9fdc0602a7742b6a7a1c6dfc92d0ab3 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-13T17:22:55Z |
| publishDate | 2019-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-e9fdc0602a7742b6a7a1c6dfc92d0ab32022-12-21T23:37:15ZengAmerican Society for MicrobiologymBio2150-75112019-04-0110210.1128/mBio.00159-19Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic AgentMelissa D. Barnes0Vijay Kumar1Christopher R. Bethel2Samir H. Moussa3John O’Donnell4Joseph D. Rutter5Caryn E. Good6Kristine M. Hujer7Andrea M. Hujer8Steve H. Marshall9Barry N. Kreiswirth10Sandra S. Richter11Philip N. Rather12Michael R. Jacobs13Krisztina M. Papp-Wallace14Focco van den Akker15Robert A. Bonomo16Louis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USADepartment of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USAEntasis Therapeutics, Waltham, Massachusetts, USAEntasis Therapeutics, Waltham, Massachusetts, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USADepartment of Pathology, University Hospitals, Cleveland Medical Center, Cleveland, Ohio, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USAPublic Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USACleveland Clinic Foundation, Cleveland, Ohio, USADepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USADepartment of Medicine, Case Western Reserve University, Cleveland, Ohio, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USADepartment of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USALouis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USAABSTRACT Multidrug-resistant (MDR) Acinetobacter spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C Acinetobacter-derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-lactamases. Importantly, OXA-like β-lactamases represent a gap in the spectrum of inhibition by recently approved β-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D β-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical Acinetobacter baumannii isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in A. baumannii. The combination of sulbactam and ETX2514 was efficacious against A. baumannii carrying blaTEM-1, blaADC-82, blaOXA-23, and blaOXA-66 in a neutropenic murine thigh infection model. We also show that, in vitro, ETX2514 inhibited ADC-7 (k2/Ki 1.0 ± 0.1 × 106 M−1 s−1) and OXA-58 (k2/Ki 2.5 ± 0.3 × 105 M−1 s−1). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D β-lactamases as well as class A and C β-lactamases and is a promising therapeutic candidate for infections caused by MDR Acinetobacter spp. IMPORTANCE The number and diversity of β-lactamases are steadily increasing. The emergence of β-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover β-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for Acinetobacter spp. producing class D β-lactamases.https://journals.asm.org/doi/10.1128/mBio.00159-19AcinetobacterDBOdiazabicyclooctanonediazabicyclooctenoneETX2514sulbactam |
| spellingShingle | Melissa D. Barnes Vijay Kumar Christopher R. Bethel Samir H. Moussa John O’Donnell Joseph D. Rutter Caryn E. Good Kristine M. Hujer Andrea M. Hujer Steve H. Marshall Barry N. Kreiswirth Sandra S. Richter Philip N. Rather Michael R. Jacobs Krisztina M. Papp-Wallace Focco van den Akker Robert A. Bonomo Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent mBio Acinetobacter DBO diazabicyclooctanone diazabicyclooctenone ETX2514 sulbactam |
| title | Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent |
| title_full | Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent |
| title_fullStr | Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent |
| title_full_unstemmed | Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent |
| title_short | Targeting Multidrug-Resistant <italic toggle="yes">Acinetobacter</italic> spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent |
| title_sort | targeting multidrug resistant italic toggle yes acinetobacter italic spp sulbactam and the diazabicyclooctenone β lactamase inhibitor etx2514 as a novel therapeutic agent |
| topic | Acinetobacter DBO diazabicyclooctanone diazabicyclooctenone ETX2514 sulbactam |
| url | https://journals.asm.org/doi/10.1128/mBio.00159-19 |
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