Identification and Evaluation of Dibasic Piperidines as Cell Wall Inhibitors against Mycobacterium tuberculosis

Globally, Mycobacterium tuberculosis remains a significant burden. Although effective treatment regimens exist, drug resistance has continued to emerge. This clinical resistance, combined with side effects and protracted treatment times from the current front-line therapies, means that 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 front-line 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 suggest that this series has potential to be developed into a viable alternative to EMB.