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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Autores principales:	Joonhyeok Choi, Ahjin Jang, Young Kyung Yoon, Yangmee Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	antimicrobial peptides antibiotics synergistic effect CRAB Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/4afe662831ee4e63ba07c0939f4ea86d
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spelling	oai:doaj.org-article:4afe662831ee4e63ba07c0939f4ea86d2021-11-25T18:40:47ZDevelopment of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection10.3390/pharmaceutics131118001999-4923https://doaj.org/article/4afe662831ee4e63ba07c0939f4ea86d2021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1800https://doaj.org/toc/1999-4923Carbapenem-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.Joonhyeok ChoiAhjin JangYoung Kyung YoonYangmee KimMDPI AGarticleantimicrobial peptidesantibioticssynergistic effectCRABPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1800, p 1800 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial peptides antibiotics synergistic effect CRAB Pharmacy and materia medica RS1-441
spellingShingle	antimicrobial peptides antibiotics synergistic effect CRAB Pharmacy and materia medica RS1-441 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
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.
format	article
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
title	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_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_sort	development of novel peptides for the antimicrobial combination therapy against carbapenem-resistant <i>acinetobacter baumannii</i> infection
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4afe662831ee4e63ba07c0939f4ea86d
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Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection

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