Antibakterielle und antivirale Wirkung des human bactericidal permeability increasing protein und hieraus abgeleiteter Peptide

Bacterial resistance to antibiotic therapy is a frequent and growing problem in medicine. Bacterial resistance factors can exert a diverse range of effects on antibiotics. These effects encompass various mechanisms, such as the enzymatic modification and the reduction of the intracellular concentration of antibiotic molecules as a result of modifications of the cell wall or active transport. Furthermore, the reconfiguration of points of attack, such as cell wall synthesis and enzyme methylation, and alterations at the cellular level, such as changes in membrane fluidity lead to antibiotic resistance as well. The most clinically relevant pathogens in this context are summarized by the WHO in the ESKAPE list, which is dominated by gram-negative bacteria. Hence, the exploration of alternative therapeutic approaches to combat bacterial infections is vital. A potential alternative is the use of antimicrobial proteins, which are produced by our immune system and represent major antimicrobial strategies of the skin and mucous membranes. What makes these antimicrobial proteins remarkable is that, despite evolutionary processes, bacteria have not yet been able to develop pan-resistance to the entire spectrum of the antimicrobial proteins. The human bactericidal permeability-increasing protein (BPI) belongs to a family of lipid-binding glycoproteins, which includes several antimicrobial proteins and is primarily to be found in neutrophil granulocytes. This study presents the first comprehensive and systematic comparison of the effects of BPI and its derived peptides on various bacterial strains. To this end, BPI was produced in Dmel-2 cells using recombinant techniques at the beginning of this research. Antimicrobial testing revealed that even pan-resistant gram-negative bacteria were susceptible to BPI, leading to significant growth inhibition of Acinetobacter spp., E. coli spp., Enterobacter cloacae, and Pseudomonas aeruginosa. A particularly remarkable finding was the resistance of Klebsiella spp. and Proteus mirabilis to BPI, which in the case of Klebsiella is most likely attributable to the very thick polysaccharide capsule of the cell wall, while in the case of Proteus is very likely based on the very long lipopolysaccharide chains, which could serve as a kind of protective shield. Among the gram-positive bacteria, an antimicrobial effect was only evident against Listeria monocytogenes, whereas staphylococci and streptococci displayed a previously described natural resistance to BPI. Although the sensitivity of Listeria to BPI has already been described, the underlying molecular mechanisms for this remain unknown. As already described in previous research, it was also observed that only the huBPI peptide exhibited an inhibitory effect against the infectivity of influenza viruses. In contrast, the recombinant huBPI showed no anti-infective effect against this virus. The reason for these disparities in the effect of BPI peptide versus recombinant protein remains unclear in this study In summary, BPI and its derived peptides exhibit potential for the development of antimicrobial agents, although primarily in the area of gram-negative bacteria. However, further analyses, such as pharmacological studies assessing the tolerability of the proteins or peptides in vivo, are still necessary. In the control of influenza infections prevention via existing vaccines plays the key role. Nevertheless, severe influenza infections are reported again and again. In this context, the BPI-derived peptide could potentially also be used against viral infections in the future. However, as with its use against bacterial infections, further trials are needed.