title: Genetically engineered lipopeptide antibiotics related to A54145 and daptomycin with improved properties.
abstract: Daptomycin is a cyclic lipopeptide antibiotic approved for the treatment of skin and skin structure infections caused by Gram-positive pathogens and for that of bacteremia and right-sided endocarditis caused by Staphylococcus aureus. Daptomycin failed to meet noninferiority criteria for the treatment of community-acquired pneumonia, likely due to sequestration in pulmonary surfactant. Many analogues of daptomycin have been generated by combinatorial biosynthesis, but only two displayed improved activity in the presence of bovine surfactant, and neither was as active as daptomycin in vitro. In the present study, we generated hybrid molecules of the structurally related lipopeptide A54145 in Streptomyces fradiae and tested them for antibacterial activity in the presence of bovine surfactant. Hybrid A54145 nonribosomal peptide synthetase (NRPS) biosynthetic genes were constructed by genetic engineering and were expressed in combination with a deletion of the lptI methyltransferase gene, which is involved in the formation of the 3-methyl-glutamic acid (3mGlu) residue at position 12. Some of the compounds were very active against S. aureus and other Gram-positive pathogens; one compound was also highly active in the presence of bovine surfactant, had low acute toxicity, and showed some efficacy against Streptococcus pneumoniae in a mouse model of pulmonary infection.
authors.affiliation: Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA.
authors.forename: Kien T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Xiaowei
authors.initials: X
authors.lastname: He
authors.forename: Dylan C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Jian-Qiao
authors.initials: JQ
authors.lastname: Gu
authors.forename: Carmela
authors.initials: C
authors.lastname: Mascio
authors.forename: Andrew
authors.initials: A
authors.lastname: Van Praagh
authors.forename: Larry
authors.initials: L
authors.lastname: Mortin
authors.forename: Min
authors.initials: M
authors.lastname: Chu
authors.forename: Jared A
authors.initials: JA
authors.lastname: Silverman
authors.forename: Paul
authors.initials: P
authors.lastname: Brian
authors.forename: Richard H
authors.initials: RH
authors.lastname: Baltz
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D017576:Daptomycin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005798:Genes, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008074:Lipoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy; D015202:Protein Engineering; D011663:Pulmonary Surfactants / Q000008:administration & dosage; D013211:Staphylococcus aureus / Q000187:drug effects; D013302:Streptomyces / Q000235:genetics
chemical_list: C065208:A54145; D000900:Anti-Bacterial Agents; D008074:Lipoproteins; D011663:Pulmonary Surfactants; D017576:Daptomycin