Antibiotic resistance is one of the greatest threats to modern medicine. Drugs that were once routinely used to treat infections are being rendered ineffective, increasing the demand for novel antibiotics with low potential for resistance. Here we report the synthesis of 18 novel cationic tetrahydroisoquinoline-triazole compounds. Five of the developed molecules were active against S. aureus at a low MIC of 2-4 μg/mL. Hit compound 4b was also found to eliminate M. tuberculosis H37Rv at MIC of 6 μg/mL. This potent molecule was found to eliminate S. aureus effectively, with no resistance observed after thirty days of sequential passaging. These results identified compound 4b and its analogues as potential candidates for further drug development that could help tackle the threat of antibiotic resistance.