Proline Hinged Amphipathic α-Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics
Soonsil Hyun, Yoonhwa Choi, Doyeon Jo, Seolah Choo, Tae Woo Park, Sujin Park, Seoyeon Kim, Seonju Lee, Sohyun Park, Sun Jin, Dae Hee Cheon, Wanki Yoo, Rekha Arya, Yong Pil Chong, Kyeong Kyu Kim, Yang Soo Kim, Yan Lee, Jaehoon Yu
Abstract
Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against Escherichia coli and hemolytic activities showed that one of the Pro-hinged peptides, KL-L9P, displays the highest specificity toward E. coli. Moreover, KL-L9P sensitizes E. coli to be responsive to most antibiotics that are not active against Gram-negative bacteria. The results of biochemical experiments show that KL-L9P promotes the rearrangement of the bacterial membrane that enables hydrophobic antibiotics to permeate. Finally, the results of animal tests demonstrate that KL-L9P strongly sensitizes Gram-negative bacteria to linezolid (Lzd), rifampicin (Rif), or clarithromycin (Clr). Thus, KL-L9P operates as a sensitizer to extend the antibacterial activity of most antibiotics to Gram-negative bacteria.