Design, synthesis, and antibacterial evaluation of PFK-158 derivatives as potent agents against drug-resistant...

Area of Science:

• Medicinal Chemistry
• Microbiology
• Pharmacology

Background:

• Antibiotic-resistant bacterial infections pose a significant global health threat.
• PFK-158 is known to potentiate polymyxin's antibacterial activity, but its intrinsic bactericidal effects are less understood.

Purpose of the Study:

• To investigate the anti-bactericidal efficacy of PFK-158 and its novel derivatives.
• To evaluate the antibacterial spectrum and potency of synthesized compounds.

Main Methods:

• Design and synthesis of PFK-158 and 35 derivatives.
• In vitro evaluation of antibacterial activities against Gram-positive and Gram-negative bacteria, including resistant strains.
• Assessment of synergistic effects with polymyxin.

Main Results:

• Compounds A1, A3, A14, A15, and B6 demonstrated significant antibacterial activity against drug-sensitive and resistant Gram-positive bacteria.
• These compounds were 2-8 times more potent than levofloxacin against Methicillin-resistant Staphylococcus epidermidis (MRSE).
• A notable synergistic effect was observed when these compounds were combined with polymyxin against drug-resistant Gram-negative bacteria.

Conclusions:

• PFK-158 derivatives possess potent intrinsic antibacterial properties, particularly against Gram-positive bacteria.
• The synthesized compounds exhibit synergistic activity with polymyxin against resistant Gram-negative bacteria.
• These findings open new avenues for developing novel therapeutics against multidrug-resistant bacterial infections.