Scheme 1. Schematic representation of the structural complexity of naturally occurring disulfide-rich cyclic peptides that are commonly used as molecular scaffolds for the development of novel antibacterial therapeutic leads. Techniques used to improve or introduce antimicrobial activities include the use of SAR introducing charged/hydrophobic or non-natural amino acids, backbone cyclization, molecular grafting, and evolution techniques. As indicated in the test, some of these engineered constructs have shown to exhibit high activity against multi-drug resistant (MDR) pathogenic bacteria. Molecular structures shown on the scheme include θ-defensins (RTD-1, pdb: 1HVZ),¹⁵⁶ BBI peptides (sunflower peptide trypsin inhibitor 1, SFTI-1, pdb: 1JBL),¹⁵⁷ α-defensins (cryptidin 4, pdb: 2GW9),¹⁵⁸ cyclotides (cycloviolacin O2, pdb: 1NBJ),¹⁵⁹ and β-hairpin antimicrobial peptides gomesin (pdb: 1KFP)¹³⁷ and porcine PG-1 (pdb: 1PG1).⁶⁷.