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

Abstract 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. Competing Interest Statement The authors have declared no competing interest. Abbreviations - SCX - Strong cation exchange - FA - Formic acid - Pet ether - petroleum ether - br - broad - NPLC - Normal phase liquid chromatography - Clint mics/heps - Intrinsic microsomal/hepatic clearance - DprE1 - Decaprenylphosphoryl-β-d-ribose 2′-epimerase - MmpL3 - Mycobacterial membrane protein Large 3 - Pks13 - Polyketide synthase 13 - atc - anhydrotetracycline - DPPC - 1,2-dipalmitoyl-sn-glycero-3-phosphocholine - Cas - Casitone - Glu - Glucose - Mol. Sieves - Molecular sieves - EMB - Ethambutol - DPPC - Dipalmitoylphosphatidylcholine - OADC - Oleic Albumin Dextrose Catalase - TB - tuberculosis - ND - not done