Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant Acinetobacter baumannii Infection.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Acinetobacter Infections/*drug therapy ; Acinetobacter baumannii/*drug effects ; Drug Resistance, Bacterial/*genetics ; Peptides/*pharmacology; Acinetobacter Infections/genetics ; Acinetobacter Infections/microbiology ; Acinetobacter baumannii/pathogenicity ; Anti-Infective Agents, Local/pharmacology ; Biofilms/drug effects ; Carbapenems/adverse effects ; Carbapenems/pharmacology ; Humans ; Microbial Sensitivity Tests

Carbapenem-resistant A. baumannii (CRAB) infection can cause acute host reactions that lead to high-fatality sepsis, making it important to develop new therapeutic options. Previously, we developed a short 9-meric peptide, Pro9-3D, with significant antibacterial and cytotoxic effects. In this study, we attempted to produce safer peptide antibiotics against CRAB by reversing the parent sequence to generate R-Pro9-3 and R-Pro9-3D. Among the tested peptides, R-Pro9-3D had the most rapid and effective antibacterial activity against Gram-negative bacteria, particularly clinical CRAB isolates. Analyses of antimicrobial mechanisms based on lipopolysaccharide (LPS)-neutralization, LPS binding, and membrane depolarization, as well as SEM ultrastructural investigations, revealed that R-Pro9-3D binds strongly to LPS and impairs the membrane integrity of CRAB by effectively permeabilizing its outer membrane. R-Pro9-3D was also less cytotoxic and had better proteolytic stability than Pro9-3D and killed biofilm forming CRAB. As an LPS-neutralizing peptide, R-Pro9-3D effectively reduced LPS-induced pro-inflammatory cytokine levels in RAW 264.7 cells. The antiseptic abilities of R-Pro9-3D were also investigated using a mouse model of CRAB-induced sepsis, which revealed that R-Pro9-3D reduced multiple organ damage and attenuated systemic infection by acting as an antibacterial and immunosuppressive agent. Thus, R-Pro9-3D displays potential as a novel antiseptic peptide for treating Gram-negative CRAB infections.

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2020R1A2C2005338 National Research Foundation of Korea; 2021R1F1A1048538 National Research Foundation of Korea

Keywords: A. baumannii; antimicrobial peptide; carbapenem-resistance; sepsis

0 (Anti-Infective Agents, Local)
0 (Carbapenems)
0 (Peptides)

Date Created: 20211127 Date Completed: 20211221 Latest Revision: 20240404

20240404

PMC8621208

10.3390/ijms222212520

34830401