colistin and 2-aminoimidazole

Antibiotic resistance has become increasingly prevalent over the past few decades, and this combined with a dearth in the development of new classes of antibiotics to treat multidrug resistant Gram-negative infections has led to a significant global health problem and the increased usage of colistin as the last resort antibiotic. Colistin, however, presents dose dependent toxicity in the clinic. One potential approach to combatting this problem is the use of an antibiotic adjuvant, a compound that is nontoxic to the bacteria that enhances the potency of colistin and ultimately allows for reducing dosing. Herein, we present a new urea-containing class of 2-aminoimidazole-based adjuvants that potentiates colistin activity against colistin-sensitive Acinetobacter baumannii. Lead compounds enabled 1000-fold reduction in the minimum inhibitory concentration of colistin in vitro and showed efficacy in a Galleria mellonella infection model, representing the first step toward validating the potential of employing these adjuvants to lower colistin dosage.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adjuvants, Pharmaceutic; Animals; Anti-Bacterial Agents; Colistin; Drug Synergism; Humans; Imidazoles; Moths

2-aminoimidazoles are an emerging class of small molecules that possess the ability to inhibit and disperse biofilms across bacterial order, class, and phylum. Herein, we report the synergistic effect between a 2-aminoimidazole/triazole conjugate and antibiotics toward dispersing preestablished biofilms, culminating with a 3-orders-of-magnitude increase of biofilm dispersion toward Staphylococcus aureus biofilms. Furthermore, we document that the 2-aminoimidazole/triazole conjugate will also resensitize multidrug-resistant strains of bacteria to the effects of conventional antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacteria; Biofilms; Calcium Chloride; Chlorides; Colistin; Drug Resistance, Bacterial; Drug Resistance, Multiple; Drug Synergism; Enterococcus faecium; Erythrocytes; Escherichia coli; Humans; Imidazoles; Magnesium; Manganese Compounds; Methicillin-Resistant Staphylococcus aureus; Novobiocin; Staphylococcus epidermidis; Tobramycin; Triazoles