Identification and Evaluation of dibasic piperidines as novel cell wall inhibitors against Mycobacterium tuberculosis

Globally, Mycobacterium tuberculosis remains a significant disease burden. Although effective treatment regimens exist, drug resistance continues to emerge. This clinical resistance, combined with side effects and protracted treatment times from the current front-line therapies, means there is a need to identify novel agents to combat this disease. Here we report on a new chemical series, identified by whole-cell phenotypic growth inhibition screening that demonstrates significant activity across multiple media. Mode of action studies indicate that this series targets the same biological pathway as Ethambutol (EMB), a drug used in the current frontline treatment of tuberculosis. Screening selected analogues against clinical isolates, resistant to EMB, demonstrated differential sensitivity both across the molecules and against the different specific resistant mutations. The data obtained suggests that this series has potential to be developed into a viable, alternative to EMB. TOC figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/702510v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1a80c05org.highwire.dtl.DTLVardef@1ad3ce9org.highwire.dtl.DTLVardef@79fe79org.highwire.dtl.DTLVardef@131ed78_HPS_FORMAT_FIGEXP M_FIG C_FIG