Murepavadin also known as POL7080 is a Pseudomonas specific peptidomimetic antibiotic. It is a synthetic cyclic beta hairpin peptidomimetic based on the cationic antimicrobial peptide protegrin I (PG-1) and the first example of an outer membrane protein-targeting antibiotic class with a novel, nonlytic mechanism of action, highly active and selective against the protein transporter LptD of Pseudomonas aeruginosa. In preclinical studies the compound was highly active on a broad panel of clinical isolates including multi-drug resistant Pseudomonas bacteria with outstanding in vivo efficacy in sepsis, lung, and thigh infection models. Intravenous murepavadin is in development for the treatment of bacterial hospital-acquired pneumonia and bacterial ventilator-associated pneumonia due to Pseudomonas aeruginosa.
Discovery and structure
The host defense antimicrobial peptide protegrin I (PG-1), exhibits broad-spectrum antimicrobial activity and good activity against multi-drug resistant Gram-negative pathogens, with a mechanism consistent with membrane disruption via pore formation. However, PG-1 exhibits unfavorable drug properties and also exhibits significant hemolysis and, as such, has limited clinical use. PG-1 contains 18 amino acids and is ordered into an anti-parallel β-strand by two disulfide bridges. A fully synthetic cyclic peptide-like molecule containing a D-proline–L-proline template grafted into a peptidomimetic scaffold to simulate and stabilize the beta hairpin conformation exhibited by PG-1 was used to generate a diverse library of peptidomimetic macrocycles which were screened for antibacterial activity. Variants in this 14-residue protein epitope mimetic (PEM) library such as the peptidomimetic L8-1 had an antimicrobial activity like that of PG-1 but with reduced hemolytic activity on human red blood cells. Iterative rounds of synthesis generated analogues with an increasingly potent and selective profile producing nanomolar range compounds specifically against Pseudomonas spp. at the expense of broad-spectrum activity. Final optimization led to the discovery of murepavadin, with remarkable Pseudomonas-specific activity in vitro and in vivo that has high plasma stability across species and is non-hemolytic at 100 µg/mL. Structure–activity relationship (SAR) studies showed that aromatic side chains of Trp2 and Trp8 are very important for antibiotic activity, while nuclear magnetic resonance studies showed that these potent D-pro-L-pro antibiotic derivatives had a stable β- hairpin conformation in aqueous solution whereas related derivatives with the D-pro-L-pro template inverted to L-pro-D-pro, shows no stable hairpin conformation and the antimicrobial activity was lost, suggesting that the β-hairpin structure is crucial for interaction with the bacterial target.
Mechanism of action
Murepavadin functions through a novel mechanism of action by binding to the lipopolysaccharide transport protein D (LptD), an outer membrane protein involved in lipopolysaccharide biogenesis in Gram-negative bacteria. By binding to LptD, murepavadin inhibit the lipopolysaccharide transport function of LptD and causes lipopolysaccharide alterations in the outer membrane of the bacterium and, ultimately, cell death.