Discovery of ultra short β-peptoids with selective activity against drug-resistant Mycobacterium tuberculosis

Abstract

There is an urgent need to develop new anti-tuberculosis (anti-TB) drugs to tackle drug-resistant strains of Mycobacterium tuberculosis (M.tb). Whereas antimicrobial peptides (AMPs) have received attention because of their antibacterial properties, oligo-N-substituted glycines (peptoids) are now seen as favorable alternatives to AMPs because they are more stable and less vulnerable to protease degradation, less expensive to produce, and better suited to potential pharmaceutical adoption and development. In this work, therefore, we designed, synthesized, and screened 22 new α- and β-peptoids against drug susceptible M. tb strain H37Rv using the Microplate Alamar Blue assay (MABA) to evaluate minimum inhibitory concentration (MIC). Eight compounds (JC5, MM2, MM5, MM9, MM10, MM11, JF11, and JF13) had MICs of less than 10 μg/ml, the most potent of which were JC5 and MM2, with MICs of 1.48 μg/ml and 2.97 μg/ml, respectively. JC5 and MM2 also retained potency against strains mono-resistant to isoniazid and rifampin, and against five of the global M. tb clade representatives. Furthermore, peptoids JC5 and MM2 showed minimum bactericidal concentration (MBC) of 3.02 μg/ml and 5.48 μg/ml respectively. Intracellular activity by luminescence showed a macrophage EC90 of less than 10 μg/ml for both JC5 and MM2. In addition, both compounds showed remarkable narrow spectrum activity. Selectivity with respect to Vero cells was modest but sufficient to consider these classes of alpha and beta-peptoids as good leads for further development of anti-TB drugs.