Antisense Peptide Nucleic Acid-Diaminobutanoic Acid Dendron Conjugates with SbmA-Independent Antimicrobial Activity against Gram-Negative Bacteria
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Antisense Peptide Nucleic Acid-Diaminobutanoic Acid Dendron Conjugates with SbmA-Independent Antimicrobial Activity against Gram-Negative Bacteria. / Iubatti, Mirko; Gabas, Isabel Maicas; Cavaco, Lina M.; Mood, Elnaz Harifi; Lim, Ernest; Bonanno, Federica; Yavari, Niloofar; Brolin, Camilla; Nielsen, Peter E.
In: ACS Infectious Diseases, Vol. 8, No. 5, 2022, p. 1098–1106.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Antisense Peptide Nucleic Acid-Diaminobutanoic Acid Dendron Conjugates with SbmA-Independent Antimicrobial Activity against Gram-Negative Bacteria
AU - Iubatti, Mirko
AU - Gabas, Isabel Maicas
AU - Cavaco, Lina M.
AU - Mood, Elnaz Harifi
AU - Lim, Ernest
AU - Bonanno, Federica
AU - Yavari, Niloofar
AU - Brolin, Camilla
AU - Nielsen, Peter E.
N1 - Publisher Copyright: © 2022 American Chemical Society. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Precision antisense antibacterial agents may be developed into novel antibiotics in the fight against multidrug-resistant Gram-negative bacteria. In this study, a series of diaminobutanoic acid (DAB) dendrons are presented as novel carriers for the delivery of antisense antibacterial peptide nucleic acids (PNAs). The dendron-PNA conjugates targeting the essential acpP gene exhibit specific antisense antimicrobial bactericidal activity against Escherichia coli and Klebsiella pneumoniae at one-digit micromolar concentrations, while showing low toxicity to human cells. One compound selected from a structure-activity relationship series showed high stability in mouse and human serum (t1/2 ≫ 24 h) as well as in vivo activity against a multidrug-resistant, extended spectrum beta-lactamase-producing E. coli in a murine peritonitis model. The compound was also well tolerated in mice upon i.v. administration up to a dose of 20 mg/kg, and in vivo fluorescence imaging indicated clearance via renal excretion with slight accumulation in the kidneys and liver. Thus, DAB-based dendrons constitute a promising new chemistry platform for development of effective delivery agents for antibacterial drugs with possible in vivo use.
AB - Precision antisense antibacterial agents may be developed into novel antibiotics in the fight against multidrug-resistant Gram-negative bacteria. In this study, a series of diaminobutanoic acid (DAB) dendrons are presented as novel carriers for the delivery of antisense antibacterial peptide nucleic acids (PNAs). The dendron-PNA conjugates targeting the essential acpP gene exhibit specific antisense antimicrobial bactericidal activity against Escherichia coli and Klebsiella pneumoniae at one-digit micromolar concentrations, while showing low toxicity to human cells. One compound selected from a structure-activity relationship series showed high stability in mouse and human serum (t1/2 ≫ 24 h) as well as in vivo activity against a multidrug-resistant, extended spectrum beta-lactamase-producing E. coli in a murine peritonitis model. The compound was also well tolerated in mice upon i.v. administration up to a dose of 20 mg/kg, and in vivo fluorescence imaging indicated clearance via renal excretion with slight accumulation in the kidneys and liver. Thus, DAB-based dendrons constitute a promising new chemistry platform for development of effective delivery agents for antibacterial drugs with possible in vivo use.
KW - antibiotics
KW - antisense
KW - dendron
KW - Gram-negative bacteria
KW - PNA
U2 - 10.1021/acsinfecdis.2c00089
DO - 10.1021/acsinfecdis.2c00089
M3 - Journal article
C2 - 35436109
AN - SCOPUS:85128861272
VL - 8
SP - 1098
EP - 1106
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
SN - 2373-8227
IS - 5
ER -
ID: 305715024