Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance

Area of Science:

• Microbiology
• Medicinal Chemistry
• Infectious Diseases

Background:

• Rising antibiotic resistance necessitates novel therapeutic strategies.
• Revisiting abandoned antimicrobial compounds offers a potential solution.
• Phosphonopeptides, like alafosfalin, were developed in the 1970s.

Purpose of the Study:

• To evaluate the antibacterial activity of alafosfalin and related phosphonopeptides.
• To assess their efficacy against multidrug-resistant bacterial isolates.
• To investigate potential synergistic interactions with existing antibiotics.

Main Methods:

• Tested alafosfalin, di-alanyl fosfalin, and β-chloro-L-alanyl-β-chloro-L-alanine against 297 bacterial isolates.
• Included carbapenemase-producing Enterobacterales (CPE), methicillin-resistant Staphylococcus aureus (MRSA), and glycopeptide-resistant enterococci (GRE).
• Examined alafosfalin-meropenem synergy against CPE isolates.

Main Results:

• Alafosfalin exhibited potent activity against CPE (MIC50: 1 mg/L, MIC90: 4 mg/L) and synergistic effects with meropenem in 16/20 isolates.
• Di-alanyl fosfalin was highly effective against glycopeptide-resistant enterococci (GRE) (MIC90: 0.5–2 mg/L).
• Moderate activity was observed against MRSA for alafosfalin (MIC90: 8 mg/L) and β-chloro-L-alanyl-β-chloro-L-alanine (MIC90: 4 mg/L).

Conclusions:

• Phosphonopeptides, particularly alafosfalin, demonstrate therapeutic potential against contemporary resistant bacterial strains.
• These compounds represent a viable option for combating infections caused by challenging pathogens like CPE and GRE.
• Further investigation into phosphonopeptides is warranted in the face of escalating antimicrobial resistance.