Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection

Abstract

bMeningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action against Neisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activity in vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected with N. meningitidis as well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activity in vivo, indicates the possibility to design peptide-based therapies for infectious diseases.

Antimicrobial activities and action mechanism studies of transportan 10 and its analogues against multidrug‐resistant bacteria

“…aureus and Neisseria meningitides ( N . meningitides ) . However, its potential use against multi‐drug resistant bacteria with high separation rates when isolated from clinics has not been reported.…”

“…Transportan 10 (TP10) is a deletion analogue of the CPP transportan, a 21-residue chimeric construct consisting of the N-terminal part of the neuropeptide galanin linked to the full-length wasp venom peptide mastoparan that lacks the toxic side effects of its parent peptide. TP10 can transport cargo across cell membranes [10,11] and it has been reported that TP10 can enter both mammalian and microbial cells, preferentially permeabilising and killing microbes such as S. aureus and Neisseria meningitides (N. meningitides) [6,9]. However, its potential use against multi-drug resistant bacteria with high separation rates when isolated from clinics has not been reported.…”

Meningococcal resistance to antimicrobial peptides is mediated by bacterial adhesion and host cell RhoA and Cdc42 signalling

“…1B), thus, rendering the bacteria resistant to physiologically relevant concentrations of LL-37 (Schaller-Bals et al, 2002). The abrogation of selective host-cell Oehlke et al (1998); Palm et al (2006); Eriksson et al (2013). b.…”

Novel antimicrobial peptide CPF‐C1 analogs with superior stabilities and activities against multidrug‐resistant bacteria

“…The ability of CPF-C1 and several of its analogs to decrease bacterial quantities was approximated in an in vivo infection example in mice using a prior established method. [30,31] In summary, female Kunming mice (18-22 g; Medical Experimental Animal Center, Lanzhou University, China) were maintained in a 12-hr light-dark cycle with an unlimited supply of water and food. The mice were challenged intraperitoneally with 1.2 × 10 8 CFU of E. coli ATCC 25922 or E. coli 780 cells in 100 μl of 0.9% NaCl (normal saline or NS).…”