Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants
In 2019, five million deaths associated with antimicrobial resistance were reported by The Centers for Disease Control and Prevention (CDC). <i>Acinetobacter baumannii</i>, a Gram-negative bacterial pathogen, is among the list of urgent threats. Previously, we reported 2-aminoimidazole (...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/12/11/1563 |
| _version_ | 1797460415755583488 |
|---|---|
| author | Ashley N. Crotteau Veronica B. Hubble Santiana A. Marrujo Anne E. Mattingly Roberta J. Melander Christian Melander |
| author_facet | Ashley N. Crotteau Veronica B. Hubble Santiana A. Marrujo Anne E. Mattingly Roberta J. Melander Christian Melander |
| author_sort | Ashley N. Crotteau |
| collection | DOAJ |
| description | In 2019, five million deaths associated with antimicrobial resistance were reported by The Centers for Disease Control and Prevention (CDC). <i>Acinetobacter baumannii</i>, a Gram-negative bacterial pathogen, is among the list of urgent threats. Previously, we reported 2-aminoimidazole (2-AI) adjuvants that potentiate macrolide activity against <i>A. baumannii</i>. In this study, we identify several of these adjuvants that sensitize <i>A. baumannii</i> to aminoglycoside antibiotics. Lead compounds <b>1</b> and <b>7</b> lower the tobramycin (TOB) minimum inhibitory concentration (MIC) against the TOB-resistant strain AB5075 from 128 μg/mL to 2 μg/mL at 30 μM. In addition, the lead compounds lower the TOB MIC against the TOB-susceptible strain AB19606 from 4 μg/mL to 1 μg/mL and 0.5 μg/mL, respectively, at 30 μM and 15 μM. The evolution of resistance to TOB and <b>1</b> in AB5075 revealed mutations in genes related to protein synthesis, the survival of bacteria under environmental stressors, bacteriophages, and proteins containing Ig-like domains. |
| first_indexed | 2024-03-09T17:05:41Z |
| format | Article |
| id | doaj.art-aae56fb03b6846dc8796944a36dc7b9d |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T17:05:41Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-aae56fb03b6846dc8796944a36dc7b9d2023-11-24T14:25:07ZengMDPI AGAntibiotics2079-63822023-10-011211156310.3390/antibiotics12111563Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole AdjuvantsAshley N. Crotteau0Veronica B. Hubble1Santiana A. Marrujo2Anne E. Mattingly3Roberta J. Melander4Christian Melander5Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USAIn 2019, five million deaths associated with antimicrobial resistance were reported by The Centers for Disease Control and Prevention (CDC). <i>Acinetobacter baumannii</i>, a Gram-negative bacterial pathogen, is among the list of urgent threats. Previously, we reported 2-aminoimidazole (2-AI) adjuvants that potentiate macrolide activity against <i>A. baumannii</i>. In this study, we identify several of these adjuvants that sensitize <i>A. baumannii</i> to aminoglycoside antibiotics. Lead compounds <b>1</b> and <b>7</b> lower the tobramycin (TOB) minimum inhibitory concentration (MIC) against the TOB-resistant strain AB5075 from 128 μg/mL to 2 μg/mL at 30 μM. In addition, the lead compounds lower the TOB MIC against the TOB-susceptible strain AB19606 from 4 μg/mL to 1 μg/mL and 0.5 μg/mL, respectively, at 30 μM and 15 μM. The evolution of resistance to TOB and <b>1</b> in AB5075 revealed mutations in genes related to protein synthesis, the survival of bacteria under environmental stressors, bacteriophages, and proteins containing Ig-like domains.https://www.mdpi.com/2079-6382/12/11/1563<i>Acinetobacter baumannii</i>antibiotic resistanceaminoglycosidesantibiotic adjuvant |
| spellingShingle | Ashley N. Crotteau Veronica B. Hubble Santiana A. Marrujo Anne E. Mattingly Roberta J. Melander Christian Melander Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants Antibiotics <i>Acinetobacter baumannii</i> antibiotic resistance aminoglycosides antibiotic adjuvant |
| title | Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants |
| title_full | Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants |
| title_fullStr | Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants |
| title_full_unstemmed | Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants |
| title_short | Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants |
| title_sort | sensitization of gram negative bacteria to aminoglycosides with 2 aminoimidazole adjuvants |
| topic | <i>Acinetobacter baumannii</i> antibiotic resistance aminoglycosides antibiotic adjuvant |
| url | https://www.mdpi.com/2079-6382/12/11/1563 |
| work_keys_str_mv | AT ashleyncrotteau sensitizationofgramnegativebacteriatoaminoglycosideswith2aminoimidazoleadjuvants AT veronicabhubble sensitizationofgramnegativebacteriatoaminoglycosideswith2aminoimidazoleadjuvants AT santianaamarrujo sensitizationofgramnegativebacteriatoaminoglycosideswith2aminoimidazoleadjuvants AT anneemattingly sensitizationofgramnegativebacteriatoaminoglycosideswith2aminoimidazoleadjuvants AT robertajmelander sensitizationofgramnegativebacteriatoaminoglycosideswith2aminoimidazoleadjuvants AT christianmelander sensitizationofgramnegativebacteriatoaminoglycosideswith2aminoimidazoleadjuvants |