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.