TY - JOUR
T1 - Toward Catalytic Antibiotics
T2 - Redesign of Fluoroquinolones to Catalytically Fragment Chromosomal DNA
AU - Goldmeier, Moshe N.
AU - Katz, Sofya
AU - Glaser, Fabian
AU - Belakhov, Valery
AU - Khononov, Alina
AU - Baasov, Timor
N1 - Publisher Copyright:
©
PY - 2021/1/15
Y1 - 2021/1/15
N2 - A library of ciprofloxacin-nuclease conjugates was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the new designer compounds (i) showed excellent in vitro hydrolytic and oxidative DNase activity, (ii) showed good antibacterial activity against both Gram-negative and Gram-positive bacteria, and (iii) proved to be highly potent bacterial DNA gyrase inhibitors via a mechanism that involves stabilization of the fluoroquinolone-topoisomerase-DNA ternary complex. Furthermore, the Cu(II) complexes of two of the new designer compounds were shown to fragment supercoiled plasmid DNA into linear DNA in the presence of DNA gyrase, demonstrating a "proof of concept"in vitro. These ciprofloxacin-nuclease conjugates can therefore serve as models with which to develop next-generation, in vivo functioning catalytic antimicrobials.
AB - A library of ciprofloxacin-nuclease conjugates was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the new designer compounds (i) showed excellent in vitro hydrolytic and oxidative DNase activity, (ii) showed good antibacterial activity against both Gram-negative and Gram-positive bacteria, and (iii) proved to be highly potent bacterial DNA gyrase inhibitors via a mechanism that involves stabilization of the fluoroquinolone-topoisomerase-DNA ternary complex. Furthermore, the Cu(II) complexes of two of the new designer compounds were shown to fragment supercoiled plasmid DNA into linear DNA in the presence of DNA gyrase, demonstrating a "proof of concept"in vitro. These ciprofloxacin-nuclease conjugates can therefore serve as models with which to develop next-generation, in vivo functioning catalytic antimicrobials.
KW - Anti-Bacterial Agents/pharmacology
KW - DNA
KW - DNA Gyrase
KW - Fluoroquinolones/pharmacology
KW - Topoisomerase II Inhibitors/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85099971745&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.0c00777
DO - 10.1021/acsinfecdis.0c00777
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C2 - 33448785
AN - SCOPUS:85099971745
SN - 2373-8227
VL - 7
SP - 608
EP - 623
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 3
ER -