Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant Acinetobacter baumannii Infection.

Ahjin Jang,Young Kyung Yoon,Yangmee Kim,Joonhyeok Choi

doi:10.3390/pharmaceutics13111800

Abstract

Carbapenem-resistant Acinetobacter baumannii (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 Ala15 or Phe18 with Ala, Phe, and Trp. PapMA-3 with Trp18 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.

Highlights

The emergence of multi-drug resistant (MDR) bacteria, combined with the failure of most antibiotic candidates in clinical trials, poses a serious threat to global public health [1,2,3]
Papiliocin is a 37-residue Antimicrobial peptides (AMPs) that was isolated from the swallowtail butterfly (Papilio xuthus) [41]; magainin 2 is a 23-residue AMP isolated from the skin of the African clawed frog (Xenopus laevis) [42,43]
The emergence of resistant strains to carbapenem, which is an important antibiotic against Gram-negative bacteria, has intensified the need for new alternatives for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) pathogens classified as critical MDR bacteria by World HealthOrganization (WHO) [2]

Summary

Introduction

The emergence of multi-drug resistant (MDR) bacteria, combined with the failure of most antibiotic candidates in clinical trials, poses a serious threat to global public health [1,2,3]. Diseases caused by Gram-negative bacteria, such as postoperative wound infection, urinary tract infection, hospital-acquired pneumonia, catheter-associated bloodstream infection, meningitis, and sepsis [4,5], have high mortality. Carbapenems such as doripenem, imipenem, and meropenem are generally considered to be the final choice of treatment for MDR Gram-negative bacteria; these bacteria have recently begun to show increased resistance to these drugs. Organization (WHO) priority list for the development of new antibiotics [6,7,8]. There is a need to accelerate the development of new antibiotic therapeutic strategies.

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Discussion

Conclusion