Antibacterial Properties of Dermaseptin S4 Derivatives with In Vivo Activity

Abstract

Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli were, respectively, 1 to 4, 1 to 4, and 1 to 16 g/ml. MICs of the short derivatives were rather similar or two to fourfold higher. Each of the three peptides was rapidly bactericidal in vitro, reducing the number of viable CFU of either E. coli or S. aureus by 6 log units in 30 min or less. Compared with MSI-78 or PG-1, K 4 -S4(1-13) was at least as potent against bacteria (assessed at two MIC multiples) but displayed lesser toxicity against human erythrocytes. Serial passage in subinhibitory concentrations led to emergence of resistance to commercial antibiotics but not to the L-or D isomer of either of the dermaseptin derivatives. The short derivatives were further investigated for antibacterial activity in vivo, using a peritonitis model of mice infected with P. aeruginosa. Naive mice in the vehicle control group exhibited 75% mortality, compared to 18 or 36% mortality in mice that received a single intraperitoneal injection (4.5 mg/kg) of K 4 -S4(1-16) or K 4 -S4(1-13), respectively. In vivo bactericidal activity was confirmed in neutropenic mice, where intraperitoneal administration of K 4 -S4(1-16) reduced the number of viable CFU in a dose-dependent manner by >3 log units within 1 h of exposure, and this was sustained for at least 5 h. Overall, the data suggest that dermaseptin S4 derivatives could be useful in treatment of infections, including infections caused by multidrug-resistant bacteria.

Direct Interaction of Dermaseptin S4 Aminoheptanoyl Derivative with Intraerythrocytic Malaria Parasite Leading to Increased Specific Antiparasitic Activity in Culture

“…was achieved at Յ4.5 mg/kg (49). Because NC7-P is less hemolytic than P, it can be assumed that it will be less toxic in vivo.…”

Synthesis and antimicrobial activity of dermaseptin S1 analogues

“…Shorter derivatives still displayed high antibacterial activity in vitro and in vivo along with a more acceptable toxicity profile against human erythrocytes, albeit still rather high. 17 In an attempt to explain why dermaseptins have markedly different biological activities despite a similar tendency to form amphipathic helices, we synthesized a series of analogues of DS1. In particular, we investigated the importance of the C-terminal portion of DS1 on the growth of several microorganisms.…”

Antibacterial Properties of Dermaseptin S4 Derivatives under Extreme Incubation Conditions

“…Many are active towards a wide range of microorganisms by a mode of action which is still not fully understood but is assumed to involve interaction with the bacterial membrane and its disruption. AMPs do not require interaction with a chiral center for activity, supporting a lower probability for microorganisms to develop efficient resistance mechanisms compared with conventional antibiotics (22,38).AMPs from the dermaseptin family were recently proposed as model peptides for investigating the effects of acyl conjugation (13,17,44). These amphibian-derived AMPs (35, 36) have been amply investigated during the past decade and shown to exert rapid cytolytic activity against a wide range of microorganisms, including gram-negative and gram-positive bacteria, protozoa, filamentous fungi (14,26,35,36), spores of pathogenic bacteria (29), yeasts (11), and intracellular parasites (13,17,30), as well as antiviral activity (5).…”