As a part of an ongoing project to develop highly potent antituberculosis therapeutics, a series novel polycyclic ‘cage’ tetra-amines were synthesized and screened for in-vitro antituberculosis activities against the H37Rv strain of tuberculosis. Three disubstituted polycyclic moieties, namely pentacyclodecane, pentacycloundecane, and tricyclodecane, were used in this study. Compounds 5 and 7 showed similar activity to SQ109 at a MIC of 1 μm while compounds 4, 6 and 8 displayed MIC activity at 1 < MIC<10 μm against H37Rv strain of tuberculosis. Compounds 5, 7 and SQ109 were selected for further screening against, multi-drug resistant, (R1097) and extensively drug resistant, (X149) strains of tuberculosis. Compound 5 showed anti-TB activity of a MIC = 1 μm against multi-drug resistant strain (R1097) and <1 μM against extensively drug resistant strain (X149) while compound 7 and SQ109 showed excellent anti-TB activity against both drug-resistant strains at a MIC <1 μm. This study demonstrates the first reported analysis of pentacyclo[5.3.0.02,5.03,9.04,8]decane as a potential therapeutic agent.