Antimicrobial Activity of Adenine-Based Inhibitors of NAD(+)-Dependent DNA Ligase

Ed T Buurman; Valerie A Laganas; Ce Feng Liu; John I Manchester

doi:10.1021/ml300169x

Antimicrobial Activity of Adenine-Based Inhibitors of NAD(+)-Dependent DNA Ligase

ACS Med Chem Lett. 2012 Jul 12;3(8):663-7. doi: 10.1021/ml300169x. eCollection 2012 Aug 9.

Authors

Ed T Buurman¹, Valerie A Laganas¹, Ce Feng Liu¹, John I Manchester¹

Affiliation

¹ Departments of Bioscience and Chemistry, AstraZeneca R&D Boston , Infection Innovative Medicines Unit, Waltham, Massachusetts 02451, United States.

Abstract

The relationship between enzyme inhibition and antimicrobial potency of adenine-based NAD(+)-dependent DNA ligase (LigA) inhibitors was investigated using a strain of the Gram-negative pathogen Haemophilus influenzae lacking its major AcrAB-TolC efflux pump and the Gram-positive pathogen Streptococcus pneumoniae. To this end, biochemical inhibitors not mediating their antibacterial mode of action (MOA) via LigA were removed from the analysis. In doing so, a significant number of compounds were identified that acted via inhibition of LigA in S. pneumoniae but not in H. influenzae, despite being inhibitors of both isozymes. Deviations from the line correlating antimicrobial and biochemical potencies of LigA inhibitors with the correct MOA were observed for both species. These deviations, usually corresponding to higher MIC/IC50 ratios, were attributed to varying compound permeance into the cell.

Keywords: LigA; antimicrobial; biochemical potency; efflux; mode of action; permeance.