Murepavadin antimicrobial activity against and resistance development in cystic fibrosis Pseudomonas aeruginosa isolates

Abstract

Background Murepavadin, a novel peptidomimetic antibiotic, is being developed as an inhalation therapy for treatment of Pseudomonas aeruginosa respiratory infection in people with cystic fibrosis (CF). It blocks the activity of the LptD protein in P. aeruginosa causing outer membrane alterations. Objectives To determine the in vitro activity of murepavadin against CF P. aeruginosa isolates and to investigate potential mechanisms of resistance. Methods MIC values were determined by both broth microdilution and agar dilution and results compared. The effect of artificial sputum and lung surfactant on in vitro activity was also measured. Spontaneous mutation frequency was estimated. Bactericidal activity was investigated using time–kill assays. Resistant mutants were studied by WGS. Results The murepavadin MIC50 was 0.125 versus 4 mg/L and the MIC90 was 2 versus 32 mg/L by broth microdilution and agar dilution, respectively. Essential agreement was >90% when determining in vitro activity with artificial sputum or lung surfactant. It was bactericidal at a concentration of 32 mg/L against 95.4% of the strains within 1–5 h. Murepavadin MICs were 2–9 two-fold dilutions higher for the mutant derivatives (0.5 to >16 mg/L) than for the parental strains. Second-step mutants were obtained for the PAO mutS reference strain with an 8×MIC increase. WGS showed mutations in genes involved in LPS biosynthesis (lpxL1, lpxL2, bamA2, lptD, lpxT and msbA). Conclusions Murepavadin characteristics, such as its specific activity against P. aeruginosa, its unique mechanism of action and its strong antimicrobial activity, encourage the further clinical evaluation of this drug.

Murepavadin, a Small Molecule Host Defense Peptide Mimetic, Activates Mast Cells via MRGPRX2 and MrgprB2

“…However, intravenous administration of murepavadin for treating nosocomial pneumonia has been temporarily halted due to reports of kidney injury. Despite this, an inhaled formulation of murepavadin is under investigation for its potential effectiveness in treating Pseudomonas infection in patients with cystic fibrosis ( 33 , 48 ). We made the novel observation that murepavadin is able to induce human MC activation through MRGPRX2 and murine MC activation through MrgprB2.…”

“…Based on these findings, we suspect that the activation of MCs via MRGPRX2/B2 confer protective immunity and contribute to host defense. The minimum concentration of murepavadin required to inhibit 90% growth of P. aeruginosa (MIC 90 ) was reported to be in the range of 2 - 32 mg/L ( 33 , 48 ). We found that murepavadin (1 µM; 1.667 mg/L) induced significant MC degranulation via MRGPRX2 and that maximal response was obtained at a concentration of 10 µM (16.67 mg/L).…”

Unveiling the Membrane and Cell Wall Action of Antimicrobial Cyclic Lipopeptides: Modulation of the Spectrum of Activity

“…Infections caused by this type of bacteria are considered a serious health threat both by the CDC and the ECDC [45,46]. In this sense, murepavadin (POL7080), a cyclic peptide that specifically kills P. aeruginosa, reached clinical phase III and it is now being evaluated as an inhalation therapy for the treatment of cystic fibrosis [47]. Altogether, the low MIC value shown by spE-10 against P. aeruginosa combined with its lower hemolytic activity compared to colistin makes this analogue an attractive hit compound to start development.…”

Peptides in BioNMR Research

“…The drug has since been developed as an inhaled formulation to treat people with cystic fibrosis. [13,14] In a follow-up study, Robinson and coworkers discovered that the already known peptide Thanatin from the spined soldier bug binds to LptA (Fig. 3B,C).…”