TY - JOUR
T1 - Targeted Antibiotic Delivery
T2 - 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.
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/6/8
Y1 - 2017/6/8
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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.7b00102
DO - 10.1021/acs.jmedchem.7b00102
M3 - Article
C2 - 28287735
AN - SCOPUS:85020376124
SN - 0022-2623
VL - 60
SP - 4577
EP - 4583
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 11
ER -