Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection
Carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infection has a high mortality rate, making the development of novel effective antibiotic therapeutic strategies highly critical. Antimicrobial peptides can outperform conventional antibiotics regarding drug resistance and broad-...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/11/1800 |
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| author | Joonhyeok Choi Ahjin Jang Young Kyung Yoon Yangmee Kim |
| author_facet | Joonhyeok Choi Ahjin Jang Young Kyung Yoon Yangmee Kim |
| author_sort | Joonhyeok Choi |
| collection | DOAJ |
| description | Carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infection has a high mortality rate, making the development of novel effective antibiotic therapeutic strategies highly critical. Antimicrobial peptides can outperform conventional antibiotics regarding drug resistance and broad-spectrum activity. PapMA, an 18-residue hybrid peptide, containing N-terminal residues of papiliocin and magainin 2, has previously demonstrated potent antibacterial activity. In this study, PapMA analogs were designed by substituting Ala<sup>15</sup> or Phe<sup>18</sup> with Ala, Phe, and Trp. PapMA-3 with Trp<sup>18</sup> showed the highest bacterial selectivity against CRAB, alongside low cytotoxicity. Biophysical studies revealed that PapMA-3 permeabilizes CRAB membrane via strong binding to LPS. To reduce toxicity via reduced antibiotic doses, while preventing the emergence of multi-drug resistant bacteria, the efficacy of PapMA-3 in combination with six selected antibiotics was evaluated against clinical CRAB isolates (C1–C5). At 25% of the minimum inhibition concentration, PapMA-3 partially depolarized the CRAB membrane and caused sufficient morphological changes, facilitating the entry of antibiotics into the bacterial cell. Combining PapMA-3 with rifampin significantly and synergistically inhibited CRAB C4 (FICI = 0.13). Meanwhile, combining PapMA-3 with vancomycin or erythromycin, both potent against Gram-positive bacteria, demonstrated remarkable synergistic antibiofilm activity against Gram-negative CRAB. This study could aid in the development of combination therapeutic approaches against CRAB. |
| first_indexed | 2024-03-10T05:08:49Z |
| format | Article |
| id | doaj.art-4afe662831ee4e63ba07c0939f4ea86d |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T05:08:49Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-4afe662831ee4e63ba07c0939f4ea86d2023-11-23T00:57:49ZengMDPI AGPharmaceutics1999-49232021-10-011311180010.3390/pharmaceutics13111800Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> InfectionJoonhyeok Choi0Ahjin Jang1Young Kyung Yoon2Yangmee Kim3Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaDivision of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaCarbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infection has a high mortality rate, making the development of novel effective antibiotic therapeutic strategies highly critical. Antimicrobial peptides can outperform conventional antibiotics regarding drug resistance and broad-spectrum activity. PapMA, an 18-residue hybrid peptide, containing N-terminal residues of papiliocin and magainin 2, has previously demonstrated potent antibacterial activity. In this study, PapMA analogs were designed by substituting Ala<sup>15</sup> or Phe<sup>18</sup> with Ala, Phe, and Trp. PapMA-3 with Trp<sup>18</sup> showed the highest bacterial selectivity against CRAB, alongside low cytotoxicity. Biophysical studies revealed that PapMA-3 permeabilizes CRAB membrane via strong binding to LPS. To reduce toxicity via reduced antibiotic doses, while preventing the emergence of multi-drug resistant bacteria, the efficacy of PapMA-3 in combination with six selected antibiotics was evaluated against clinical CRAB isolates (C1–C5). At 25% of the minimum inhibition concentration, PapMA-3 partially depolarized the CRAB membrane and caused sufficient morphological changes, facilitating the entry of antibiotics into the bacterial cell. Combining PapMA-3 with rifampin significantly and synergistically inhibited CRAB C4 (FICI = 0.13). Meanwhile, combining PapMA-3 with vancomycin or erythromycin, both potent against Gram-positive bacteria, demonstrated remarkable synergistic antibiofilm activity against Gram-negative CRAB. This study could aid in the development of combination therapeutic approaches against CRAB.https://www.mdpi.com/1999-4923/13/11/1800antimicrobial peptidesantibioticssynergistic effectCRAB |
| spellingShingle | Joonhyeok Choi Ahjin Jang Young Kyung Yoon Yangmee Kim Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection Pharmaceutics antimicrobial peptides antibiotics synergistic effect CRAB |
| title | Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_full | Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_fullStr | Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_full_unstemmed | Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_short | Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_sort | development of novel peptides for the antimicrobial combination therapy against carbapenem resistant i acinetobacter baumannii i infection |
| topic | antimicrobial peptides antibiotics synergistic effect CRAB |
| url | https://www.mdpi.com/1999-4923/13/11/1800 |
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