Small Molecule Alkynyl-Phenylaminoguanidines: A New Weapon Against Multi-Drug Resistant Bacteria

Abstract

The coexistence of Gram-negative organisms, such as Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) in diabetic foot ulcers poses significant therapeutic challenges and increases the rate of treatment failure. By studying the structure-activity relationships of small alkynylphenyl-aminoguanidine molecules, we identified heptyne and octyne derivatives as promising antibacterial agents. These compounds exhibited potent activity against Gram-positive MRSA USA300 (MIC = 0.5 µg/mL) and reasonable activity against Gram-negative A. baumannii AB5075 (MIC = 8 µg/mL). It is noteworthy that octynylphenyl-aminoguanidine demonstrated a rapid bactericidal effect within 2 h and showed no evidence of resistance development. Despite systemic intolerance, topical application of the two most active compounds significantly improved skin condition and reduced bacterial burdens in an murine skin infection model (MRSA). These results highlight a promising therapeutic avenue for MRSA skin infections, with potential efficacy in coinfections with multidrug-resistant Gram-negative pathogens such as A. baumannii.