Peptides with dual mode of action: Killing bacteria and preventing endotoxin-induced sepsis

Abstract

Bacterial infections, with the most severe form being sepsis, can often not be treated adequately leading to high morbidity and lethality of infected patients in critical care units. In particular, the increase in resistant bacterial strains and the lack of new antibiotics are main reasons for the worsening of the current situation, As a new approach, the use of antimicrobial peptides (AMPs) seems to be promising, combining the ability of broad-spectrum bactericidal activity and low potential of induction of resistance. Peptides based on natural defense proteins or polypeptides such as lactoferrin, Limulus anti-lipopolysaccharide factor (LALF), cathelicidins, and granulysins are candidates due to their high affinity to bacteria and to their pathogenicity factors, in first line lipopolysaccharide (LPS, endotoxin) of Gram-negative origin. In this review, we discuss literature with the focus on the use of AMPs from natural sources and their variants as antibacterial as well as anti-endotoxin (anti-inflammatory) drugs. Considerable progress has been made by the design of new AMPs for acting efficiently against the LPS-induced inflammation reaction in vitro as well as in vivo (mouse) models of sepsis. Furthermore, the data indicate that efficient antibacterial compounds are not necessarily equally efficient as anti-endotoxin drugs and vice versa. The most important reason for this may be the different molecular geometry of LPS in bacteria and in free form. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

Immunomodulatory effects of anti-microbial peptides

“…They also upregulate angiogenesis and downregulate toxin production. All these activities likely work independently; efficient AMPs are not necessarily active as anti-endotoxin therapies and vice versa [104]. In turn, the pleiotropic functions require a drug development design process that is more complex than that with drugs having only single functions (and minor side effects).…”

Structural properties of bioactive peptides with α‐glucosidase inhibitory activity

“…[10,11] Bioactive peptides are commonly specific fragments of proteins that elicit biological activity and consequently modulate the health status of individuals. Some of the reported bioactivities elicited by bioactive peptides include antibacterial, [13][14][15] antifungal, [16] anti-inflammatory, [17,18] antioxidant, and angiotensin-converting enzyme (ACE) inhibitory activities. This is evident by the propensity of databases and repositories containing huge amount of data on bioactive peptide structure, properties, and activities.…”

Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

“…Lipopolysaccharide (LPS) is a major structural component of the Gram-negative bacterial outer membrane and protects bacteria from antimicrobial compounds [11, 30]. LPS from E. coli and other gram-negative bacteria is the endotoxin and activates innate immunity through binding TLR4 receptors [39]. The overall positive charge on cationic antimicrobial peptides assists them to form strong electrostatic interactions with the negatively charged LPS in the membrane of Gram-negative bacteria neutralizing the overall negative charge [40, 41].…”