Proline-Hinged α‑Helical Peptides Sensitize Gram-Positive Antibiotics, Expanding Their Physicochemical Properties to Be Used as Gram-Negative Antibiotics

The outer membrane (OM) of Gram-negative bacteria is the most difficult obstacle for small-molecule antibiotics to reach their targets in the cytosol. The molecular features of Gram-negative antibiotics required for passing through the OM are that they should be positively charged rather than neutral, flat rather than globular, less flexible, or more increased amphiphilic moment. Because of these specific molecular characteristics, developing Gram-negative antibiotics is difficult. We focused on sensitizer peptides to facilitate the passage of hydrophobic Gram-positive antibiotics through the OM. We explored ways of improving the sensitizing ability of proline-hinged α-helical peptides by adjusting their length, hydrophobicity, and N-terminal groups. A novel peptide, 1403, improves the potentiation of rifampicin in vitro and in vivo and potentiates most Gram-positive antibiotics. The “sensitizer” approach is more plausible than those that rely on conventional drug discovery methods concerning drug development costs and the development of drug resistance.