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Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo.
J Med Chem. 2017 06 08; 60(11):4577-4583.JM

Abstract

In order to address the dire need for new antibiotics to treat specific strains of drug resistant Gram-negative bacterial infections, a mixed ligand analog of the natural Acinetobacter baumannii selective siderophore, fimsbactin, was coupled to daptomycin, a Gram-positive only antibiotic. The resulting conjugate 11 has potent activity against multidrug resistant strains of A. baumannii both in vitro and in vivo. The study also indicates that conjugation of siderophores to "drugs" that are much larger than the siderophore (iron transport agent) itself facilitates active uptake that circumvents the normal permeability problems in Gram-negative bacteria. The results demonstrate the ability to extend activity of a normally Gram-positive only antibiotic to create a potent and targeted Gram-negative antibiotic using a bacterial iron transport based sideromycin Trojan horse strategy.

Authors+Show Affiliations

Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States. Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.Hsiri Therapeutics, LLC , Rosetree Corporate Center, 1400 N. Providence Road, Building 1, Suite 115S, Media, Pennsylvania 19063, United States.Frieman Life Sciences Center, University of Notre Dame , Notre Dame, Indiana 46556, United States.Frieman Life Sciences Center, University of Notre Dame , Notre Dame, Indiana 46556, United States.Frieman Life Sciences Center, University of Notre Dame , Notre Dame, Indiana 46556, United States.PracticaChem , 5 Lanyuan Road, Room D-603, Huayuan Industrial Park, Tianjin, 300384, China.PracticaChem , 5 Lanyuan Road, Room D-603, Huayuan Industrial Park, Tianjin, 300384, China.PracticaChem , 5 Lanyuan Road, Room D-603, Huayuan Industrial Park, Tianjin, 300384, China.Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States. Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

28287735

Citation

Ghosh, Manuka, et al. "Targeted Antibiotic Delivery: Selective Siderophore Conjugation With Daptomycin Confers Potent Activity Against Multidrug Resistant Acinetobacter Baumannii Both in Vitro and in Vivo." Journal of Medicinal Chemistry, vol. 60, no. 11, 2017, pp. 4577-4583.
Ghosh M, Miller PA, Möllmann U, et al. Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo. J Med Chem. 2017;60(11):4577-4583.
Ghosh, M., Miller, P. A., Möllmann, U., Claypool, W. D., Schroeder, V. A., Wolter, W. R., Suckow, M., Yu, H., Li, S., Huang, W., Zajicek, J., & Miller, M. J. (2017). Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo. Journal of Medicinal Chemistry, 60(11), 4577-4583. https://doi.org/10.1021/acs.jmedchem.7b00102
Ghosh M, et al. Targeted Antibiotic Delivery: Selective Siderophore Conjugation With Daptomycin Confers Potent Activity Against Multidrug Resistant Acinetobacter Baumannii Both in Vitro and in Vivo. J Med Chem. 2017 06 8;60(11):4577-4583. PubMed PMID: 28287735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo. AU - Ghosh,Manuka, AU - Miller,Patricia A, AU - Möllmann,Ute, AU - Claypool,William D, AU - Schroeder,Valerie A, AU - Wolter,William R, AU - Suckow,Mark, AU - Yu,Honglin, AU - Li,Shuang, AU - Huang,Weiqiang, AU - Zajicek,Jaroslav, AU - Miller,Marvin J, Y1 - 2017/04/01/ PY - 2017/3/14/pubmed PY - 2017/7/5/medline PY - 2017/3/14/entrez SP - 4577 EP - 4583 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 60 IS - 11 N2 - In order to address the dire need for new antibiotics to treat specific strains of drug resistant Gram-negative bacterial infections, a mixed ligand analog of the natural Acinetobacter baumannii selective siderophore, fimsbactin, was coupled to daptomycin, a Gram-positive only antibiotic. The resulting conjugate 11 has potent activity against multidrug resistant strains of A. baumannii both in vitro and in vivo. The study also indicates that conjugation of siderophores to "drugs" that are much larger than the siderophore (iron transport agent) itself facilitates active uptake that circumvents the normal permeability problems in Gram-negative bacteria. The results demonstrate the ability to extend activity of a normally Gram-positive only antibiotic to create a potent and targeted Gram-negative antibiotic using a bacterial iron transport based sideromycin Trojan horse strategy. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/28287735/Targeted_Antibiotic_Delivery:_Selective_Siderophore_Conjugation_with_Daptomycin_Confers_Potent_Activity_against_Multidrug_Resistant_Acinetobacter_baumannii_Both_in_Vitro_and_in_Vivo_ L2 - https://dx.doi.org/10.1021/acs.jmedchem.7b00102 DB - PRIME DP - Unbound Medicine ER -