Hydrophobic modification Thr of polymyxin E: Effect on activity and toxicity

Growing multidrug bacterial resistance has become a life-threatening problem. Polymyxins are a “last resort” antibiotic against Gram-negative bacteria (Gram-ne − ), but exhibit weak activity against Gram-positive bacteria (Gram-po + ) caused by different bacterial membrane structures. Herein, it is proposed that the challenge can be overcome by hydrophobically modified polymyxin E for enhancing the hydrophobic interaction with the membrane. After synthesizing mono-and di-fatty acyl conjugates to Thr residues of polymyxin E, seven new polymyxin analogs were screened out with in vitro activity against Gram-ne − and Gram-po + . Among them, di-caprylic acid-modified (comp. 2 ) and mono-linoleic acid-modified (comp. 3) compounds with the most potent activity against both bacteria. Moreover, the membrane research showed that polymyxin analogs obtain activity against Gram-po + by higher ability to dispute cell membrane and wall than polymyxin E. Additionally, the results showed a trend of increasing hydrophobicity of analogs showing the tendency to rise up at the beginning and declining in later against Gram-po + and gradually decreasing activity against Gram-ne − , hence, we speculated that controlling Log P at 1–3 helps to obtain broad-spectrum antibiotic. Crucially, the maximum tolerated doses (MTD) of analogs were significantly higher than polymyxin E, and reduced the nephrotoxicity. As expected, hydrophobic modification polymyxin E not only enhance the activity of Gram-po + , but also could retain the activity of Gram-ne − . This study offers more insights into the synthesis of new antibiotics based on polymyxin E structure, especially broad-spectrum antibiotics.