pyrromethene-546 and Chlamydia-Infections

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 ≤ 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 μM. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

Topics: Anti-Bacterial Agents; Chlamydia Infections; Chlamydia trachomatis; Dose-Response Relationship, Drug; HeLa Cells; Humans; Microbial Sensitivity Tests; Microbial Viability; Molecular Structure; Pyridones; Structure-Activity Relationship; Thiazoles; Tumor Cells, Cultured