Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

Area of Science:

• Microbiology
• Infectious Diseases
• Medicinal Chemistry

Background:

• Rising multi-drug resistant Gram-negative bacterial infections necessitate last-resort antibiotics like polymyxins.
• Polymyxin therapy is hindered by significant toxicities, particularly nephrotoxicity.
• Previous work introduced semisynthetic polymyxins with reduced toxicity by modifying the N-terminus.

Purpose of the Study:

• To explore modifications adjacent to the polymyxin macrocycle to further reduce toxicity.
• To identify novel semisynthetic polymyxins with potent antibacterial activity and improved safety profiles.
• To evaluate the synergistic potential of new polymyxins with other antibiotics against resistant bacteria.

Main Methods:

• Synthesis of novel semisynthetic polymyxins with variations in amino acid residues near the macrocycle.
• Assessment of antibacterial activity against Gram-negative bacteria, including polymyxin-resistant strains.
• Evaluation of toxicity in human proximal tubule epithelial cells.
• Testing for synergistic effects with novobiocin, rifampicin, and erythromycin against mcr-positive E. coli.

Main Results:

• Identification of new semisynthetic polymyxins retaining potent antibacterial activity comparable to polymyxin B.
• Demonstrated further reduction in toxicity towards human proximal tubule epithelial cells compared to previous analogs.
• Effective synergy observed between the novel polymyxins and novobiocin, rifampicin, or erythromycin against mcr-positive, polymyxin-resistant E. coli.

Conclusions:

• Modifying amino acid residues adjacent to the polymyxin macrocycle yields potent, less toxic semisynthetic derivatives.
• These novel polymyxins offer a promising therapeutic strategy against challenging multi-drug resistant Gram-negative infections.
• The synergistic potential against polymyxin-resistant strains presents a viable approach to overcome resistance mechanisms.