Abstract
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.
Highlights
Gram-negative sepsis is caused by an unregulated immune response to infection in which immune cells are activated by lipopolysaccharide (LPS) produced from the bacterial outer membrane, resulting in severe inflammation, organ failure, and even death [1,2]
The term “ESKAPE” comprises six highly antibiotic-resistant pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, which account for the majority of bacteremia cases and surgical-site infections in healthcare settings [3]
The clinical application of Antimicrobial peptides (AMPs) is limited by their propensity for enzymatic degradation [51]; peptides with D-amino acid substitutions are completely resistant to proteolytic degradation in vivo, ensuring maximum bioavailability and therapeutic efficacy [52]
Summary
Gram-negative sepsis is caused by an unregulated immune response to infection in which immune cells are activated by lipopolysaccharide (LPS) produced from the bacterial outer membrane, resulting in severe inflammation, organ failure, and even death [1,2]. The term “ESKAPE” comprises six highly antibiotic-resistant pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, which account for the majority of bacteremia cases and surgical-site infections in healthcare settings [3]. A. baumannii has been identified as a significant opportunistic pathogen that causes lethal sepsis with a high death rate in hospitals [4] It infects roughly 1 million individuals each year, and 44% of clinical isolates are multidrug-resistant (MDR) A. baumannii [5,6]. Some of the most common mechanisms of resistance in these isolates include penicillin-binding protein mutations, porin loss, antibiotic target site mutations, and efflux pump overexpression [8]
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