Human defensin-inspired discovery of peptidomimetic antibiotics

Antibiotics with multiple mechanisms of action and broad-spectrum are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. Combining computational and medicinal chemistry tools, we used the structure of human α-defensin 5 (HD5) to design a class of peptidomimetic antibiotics with improved activity against both gram-negative and gram-positive bacteria. The most promising lead, compound 10, showed potent killing of multiple drug-resistant gram-negative bacteria isolated from patients. Compound 10 exhibited a multiplex mechanism of action through targeting membrane components—outer membrane protein A and lipopolysaccharide, as well as a potential intracellular target—70S ribosome, thus causing membrane perturbation and inhibition of protein synthesis. In vivo efficacy, stability, and safety of compound 10 were also validated. This human defensin-inspired synthetic peptidomimetic could help solve the serious problem of drug resistance to conventional antibiotics.