טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentKatz Sofya
SubjectTowards Catalytic Antibiotics - Catalytic Fluoroquinolones
DepartmentDepartment of Chemistry
Supervisor Professor Timor Baasov
Full Thesis textFull thesis text - English Version


Abstract

Fluoroquinolones are highly potent, broad spectrum antibiotics that are among the most commonly prescribed antibacterials in the world. They selectively bind to the bacterial topoisomerase IIA-DNA complex and exert bactericidal effect by causing fragmentation of the bacterial chromosome. However, due to the rapid emergence of resistance to fluoroquinolones, it has become clear there is an urgent need to develop truly novel, more advanced strategies for combating bacterial resistance. One such strategy is developing catalytic antibiotics.

The catalytic antibiotic strategy seeks to mediate catalytic inactivation of the therapeutic target to form an inactive or dysfunctional entity. The possible benefits of this approach include increased potency, activity against resistant bacteria and reduced potential for the development of new resistance. On the basis of published structural and mechanistic data about the topoisomerase IIA targets and about artificial nuclease systems we have rationally designed several ciprofloxacin-nuclease agents with potential to cleave a specific phosphodiester bond within the bacterial topoisomerase IIA-DNA complex, in such a manner as to cause rapid bacterial chromosome fragmentation and consequently a bactericidal effect at very low doses.

The ciprofloxacin-nuclease agents synthesized to date contain a Cu(II)-cyclen system linked via a hydrophobic aliphatic or aromatic linker to the piperazine ring of ciprofloxacin. These compounds were found to be potent DNA gyrase inhibitors and to preserve ciprofloxacin’s ability to stabilize gyrase-DNA cleavage complex but were unsuccessful in catalysing DNA hydrolysis within the cleavage complex as it was expected. Further attempts to improve the initial design and to achieve the desired catalytic activity are currently being made by our research group.