Antibiotic resistance is increasing at an alarming rate, especially in the case of M. tuberculosis. Alternatives to traditional antibiotics are urgently needed to combat these resistant bacteria. Disrupting bacterial, but not mammalian, outer-membrane integrity with peptides is one such strategy to destroy toxic bacteria in a highly selective manner. Design strategies to develop potent, stable antimicrobial peptides stemming from a fundamental understanding of their mechanism of cell disruption are urgently needed. In response, novel anti-microbial peptides with inhibitory activity against M. tuberculosis and streptococcus bacteria were developed, as well as an innovative, de novo method for creating the antimicrobial peptides using bioinformatics filtering and structurally informed rational design. These peptides can find utility in the treatment of and prevention of tuberculosis infection, tuberculosis disease, and streptococcal infections.