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PMID: 20086142 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Genetically engineered lipopeptide antibiotics related to A54145 and daptomycin with improved properties.

Antimicrobial agents and chemotherapy ·Vol. 54 ·No. 4 ·2010-04-00 ·Pages 1404-13

Nguyen KT, He X, Alexander DC, Li C, Gu JQ, Mascio C, Van Praagh A, Mortin L, Chu M, Silverman JA, Brian P, Baltz RH

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.

MeSH Terms
Animals Anti-Bacterial Agents/biosynthesis,chemistry,pharmacology Cattle Daptomycin/analogs & derivatives,biosynthesis,chemistry,pharmacology Female Genes, Bacterial Gram-Positive Bacteria/drug effects Lipoproteins/biosynthesis,chemistry,genetics,pharmacology Mice Microbial Sensitivity Tests Molecular Structure Pneumonia, Pneumococcal/drug therapy Protein Engineering Pulmonary Surfactants/administration & dosage Staphylococcus aureus/drug effects Streptomyces/genetics
Chemicals
A54145 Anti-Bacterial Agents Lipoproteins Pulmonary Surfactants Daptomycin
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Nguyen Kien T
Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA.
He Xiaowei
Alexander Dylan C
Li Chen
Gu Jian-Qiao
Mascio Carmela
Van Praagh Andrew
Mortin Larry
Chu Min
Silverman Jared A
Brian Paul
Baltz Richard H
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Article Info
Journal
Antimicrobial agents and chemotherapy
Abbr.
Antimicrob Agents Chemother
ISSN
1098-6596
DOI
10.1128/AAC.01307-09
Published
2010-04-00
Epub
2010-00-19
Pages
1404-13
Language
English
Region
United States
NLM ID
0315061
PMCID
PMC2849371
Subset
IM
Grants
NIGMS NIH HHS · R44 GM068173 · United States
NIGMS NIH HHS · 2 R44 GM068173-08 · United States
External Links
PubMed source DOI: 10.1128/AAC.01307-09 PMC Full Text View journal details
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