Noncytotoxic polymyxin derivatives enhance antibiotic action against multidrug-resistant Gram-negative bacteria

Area of Science:

• Pharmacology
• Microbiology
• Medicinal Chemistry

Background:

• Multidrug-resistant (MDR) Gram-negative bacteria pose a significant global health threat, necessitating novel therapeutic strategies.
• Polymyxins are re-emerging antibiotics, but their clinical use is limited by nephrotoxicity and neurotoxicity.
• Development of safer polymyxin derivatives as potentiators is crucial for overcoming antibiotic resistance.

Purpose of the Study:

• To synthesize and evaluate safer polymyxin B derivatives as antibiotic potentiators.
• To assess the synergistic activity of compound 1 with various antibiotics against MDR Gram-negative bacteria.
• To investigate the potential of compound 1 in restoring susceptibility to existing antibiotics.

Main Methods:

• Synthesis of polymyxin B3 derivatives, including compound 1.
• In vitro evaluation of compound 1's toxicity to kidney cells.
• Determination of minimum inhibitory concentrations (MICs) for various antibiotic combinations against MDR Gram-negative pathogens.
• Assessment of compound 1's outer membrane permeabilization properties.

Main Results:

• Compound 1, a non-nephrotoxic polymyxin derivative, demonstrated promising outer membrane permeabilization.
• Compound 1 synergized with six different antibiotic classes against MDR Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae.
• Compound 1 lowered MICs of rifampicin, zoliflodacin, and pristinamycin below susceptibility breakpoints.
• A combination of zoliflodacin and compound 1 showed potent bactericidal activity against MDR P. aeruginosa and A. baumannii.

Conclusions:

• Compound 1 is a safe and effective potentiator for multiple antibiotics against MDR Gram-negative bacteria.
• This novel polymyxin derivative broadens the activity spectrum of existing antibiotics, offering a viable strategy to combat resistance.
• The combination of zoliflodacin and compound 1 represents a promising therapeutic approach for difficult-to-treat Gram-negative infections.