Title:Designing Type II Topoisomerase Inhibitors: A Molecular Modeling Approach
Volume: 14
Issue: 1
Author(s): Juan J. Perez, Cecylia S. Lupala and Patricia Gomez-Gutierrez
Affiliation:
Keywords:
Topoisomerases inhibitors, antibiotics design, nosocomial infections, quinolones.
Abstract: Nosocomial infections are produced by pathogens with the ability to persist in hospital environments and with
the propensity to develop resistance to diverse antimicrobials. In order to tackle resistance, it has been pointed as good
strategy to select resilient drug targets that are evolutionally constrained to design drugs less susceptible to develop resistance.
Molecular modeling can help to fulfill this goal by providing a rationalization of the observed resistance at the molecular
level and, suggesting modifications on existing drugs or in the design of new ones to overcome the problem. The
present report focus on type II topoisomerases, a clinical validated target for antibacterials and describe diverse modes of
intervention including, inhibition of their ATPase function, stabilization of the cleavage complex or prevention of DNA
strand hydrolysis. Moreover, the origin of resistance is also rationalized on the base of ligand-target interactions. Finally,
efforts are described to circumvent the effect of non-susceptible strains by the design of new drugs based on existing ones,
like the case of diones that act through the same mechanism as quinolones or the newly released quinole-carbonitrile derivatives
that inhibit type II topoisomerases through a new mechanism.
