Murepavadin

Murepavadin also known as POL7080 is a Pseudomonas specific peptidomimetic antibiotic.[1] 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.[2] 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.[3] Intravenous murepavadin is in development [1] for the treatment of bacterial hospital-acquired pneumonia and bacterial ventilator-associated pneumonia due to Pseudomonas aeruginosa.

Murepavadin
Clinical data
Other namesPOL7080
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC73H112N22O16
Molar mass1553.837 g·mol−1
3D model (JSmol)

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.[4][5][6][7] 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.[4][5] 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.[8] Final optimization led to the discovery of murepavadin,[1][2] 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,[9] 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,[9] suggesting that the β-hairpin structure is crucial for interaction with the bacterial target.

Design of a novel synthetic cyclic beta hairpin peptidomimetic based on the cationic antimicrobial peptide protegrin I

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.[2] 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.

Spectrum of activity

Murepavadin exhibits a specific and potent bactericidal activity in vitro against Pseudomonas aeruginosa including carbapenemase-producing and colistin-resistant isolates and was shown to be largely inactive against other Gram-negative bacteria, and Gram-positive bacteria. When tested in a large minimum inhibitory concentration surveillance study, against 1219 contemporary clinical isolates from the USA, Europe, and China of which 28% were multi-drug resistant strains, murepavadin exhibited a potent antimicrobial activity having a minimum inhibitory concentration for 90% of strains of 0.12 mg/L.[1] There were no significant differences between geographic locations, and there was little difference in activity between multi-drug resistant/and non-multi-drug resistant isolates and no cross-resistance was observed with any other antimicrobial tested which supports its novel mechanism of action. Murepavadin showed outstanding in vivo efficacy in mouse sepsis (ED50 of 0.25 - 0.55 mg/kg) and lung and thigh infection models. It displays linear pharmacokinetics, is dose proportional with a good penetration into the epithelial lung fluid which underscores its potent in vivo activity in lung infection models including extensively drug-resistant isolates. In phase I clinical trial in healthy volunteers, single doses were well tolerated at plasma concentrations expected to meet or exceed efficacious levels, with no serious adverse events reported.[3] The favorable in vitro and in vivo properties of murepavadin combined with an appropriate safety pharmacology and toxicology profile led to the clinical development of murepavadin for the treatment of serious infections caused by Pseudomonas aeruginosa. Murepavadin successfully completed phase-II clinical tests in hospital patients with life-threatening Pseudomonas lung infections[8] and is in phase III development for the treatment of bacterial hospital-acquired and ventilator-associated bacterial due to Pseudomonas aeruginosa infection.[1]

References
  1. Martin-Loeches I, Dale GE, Torres A (February 2018). "Murepavadin: a new antibiotic class in the pipeline". Expert Review of Anti-infective Therapy. 16 (4): 259–268. doi:10.1080/14787210.2018.1441024. PMID 29451043.
  2. Srinivas N, Jetter P, Ueberbacher BJ, Werneburg M, Zerbe K, Steinmann J, Van der Meijden B, Bernardini F, Lederer A, Dias RL, Misson PE, Henze H, Zumbrunn J, Gombert FO, Obrecht D, Hunziker P, Schauer S, Ziegler U, Kach A, Eberl L, Riedel K, DeMarco SJ, Robinson JA (February 2010). "Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa" (PDF). Science. 327 (5968): 1010–1013. doi:10.1126/science.1182749. PMID 20167788.
  3. Wach A, Dembowsky K, Dale GE (April 2018). "Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses". Antimicrobial Agents and Chemotherapy. 62 (4): e02355-17. doi:10.1128/AAC.02355-17. PMC 5913942. PMID 29437621.
  4. Shankaramma SC, Athanassiou Z, Zerbe O, Moehle K, Mouton C, Bernardini F, Vrijbloed JW, Obrecht D, Robinson JA (November 2002). "Macrocyclic hairpin mimetics of the cationic antimicrobial peptide protegrin I: a new family of broad‐spectrum antibiotics". ChemBioChem. 3 (11): 1126−1133. doi:10.1002/1439-7633(20021104)3:11<1126::AID-CBIC1126>3.0.CO;2-I. PMID 12404639.
  5. Robinson JA, Shankaramma SC, Jetter P, Kienzl U, Schwendener RA, Vrijbloed JW, Obrecht D (March 2005). "Properties and structure–activity studies of cyclic β-hairpin peptidomimetics based on the cationic antimicrobial peptide protegrin I". Bioorganic & Medicinal Chemistry. 13 (6): 2055–2064. doi:10.1016/j.bmc.2005.01.009. PMID 15727859.
  6. Luther A, Moehle K, Chevalier E, Dale G, Obrecht D (January 2011). "Emerging new therapeutics against key Gram-negative pathogens". Annual Reports in Medicinal Chemistry. 46: 245–262. doi:10.1016/B978-0-12-386009-5.00012-6. ISBN 9780123860095.
  7. Robinson JA, Shankaramma SC, Jetter P, Kienzl U, Schwendener RA, Vrijbloed JW, Obrecht D (June 2017). "Protein epitope mimetic macrocycles as biopharmaceuticals". Current Opinion in Chemical Biology. 38: 45–51. doi:10.1016/j.cbpa.2017.02.004. PMID 28319811.
  8. Zerbe K, Moehle K, Robinson JA (June 2017). "Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines". Accounts of Chemical Research. 50 (6): 1323−1331. doi:10.1021/acs.accounts.7b00129. PMID 28570824.
  9. Schmidt J, Patora-Komisarska K, Moehle K, Obrecht D, Robinson JA (September 2013). "Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp" (PDF). Bioorganic & Medicinal Chemistry. 21 (18): 5806−5810. doi:10.1016/j.bmc.2013.07.013. PMID 23932450.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.