Nylon-3 copolymers containing both hydrophobic and cationic subunits can mimic the activity profile of host-defense peptides, if subunit identity and proportion are carefully selected. These sequence- and stereo-random copolymers inhibit bacterial growth at relatively low concentrations, apparently via disruption of bacterial membranes, but they are relatively nondisruptive toward eukaryotic cell membranes (low hemolytic activity). In all previous examples, the hydrophobic subunits have contained cycloalkyl groups that incorporate the backbone Cα–Cβ bond. Here we have explored the effects of using analogous acyclic hydrophobic subunits. The results indicate that replacing cyclic with acyclic hydrophobic subunits has a modest influence on biological properties. This influence appears to arise from differences in subunit flexibility.