The existence of multidrug-resistant pathogenic bacteria presents a growing problem in the world. To extend the lifespan of existing antibiotics, one possibility is to inhibit the relevant enzyme responsible for antibiotic resistance to restore the effectiveness of the antibiotic. Aminoglycoside 6'-acetyltransferase type Ib (abbreviated AAC(6')-Ib) is a particularly widespread resistance enzyme in high priority pathogens, providing resistance towards powerful aminoglycoside antibiotics. Three compounds previously tested as potential inhibitors of AAC(6')-Ib and 12 compounds similar in structure were synthesized to examine their effectiveness at inhibiting the growth of Acinetobacter baumanniiA155 expressing AAC(6')-Ib when used in combination with amikacin. This was done to determine how modifying the pyrrolidine pentamine scaffold of these compounds affected their inhibition of A155 growth and if any of the 12 new compounds could serve as a more robust potential lead compound. Ultimately, while none of the 12 new compounds proved more effective as inhibitors than the compounds previously identified, the modifications demonstrated the relevant importance of the R1 group and the possibility for further improvement. Cytotoxicity assays identified toxicity to the host as a factor to consider for one of the new compounds and also confirmed correlation between molecular docking values and potentiation.
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