Aminoglycosides, antibiotics used to treat gram-negative bacterial infections, are becoming less viable due to the rise and dissemination of antibiotic resistance mediated by aminoglycoside modifying enzymes (AMEs). One of the most clinically relevant AMEs is aminoglycoside 6’-N-acetyltransferase type Ib [AAC(6’)-Ib]. Aminoglycoside resistance due to AAC(6’)-Ib can be surmounted by the use of inhibitors. Here, two different methodologies were employed to identify AAC(6’)-Ib inhibitors: 1) the use of zinc and copper pyrithione (ZnPT and CuPT, respectively), and 2) using the Glide molecular docking program. Inhibitor potency was determined using colorimetric enzyme assays and growth curves on bacteria of clinical relevance. The addition of ZnPT or CuPT in combination with amikacin (AK) greatly reduced the resistance levels of AK-resistant Klebsiella pneuomoniae JHCK1. With Glide, 1-[3-2(aminoethyl)-benzyl]-3-(piperidin-1-ylmethyl)pyrrolidin-3-ol] (compound 1), was found to inhibit the acetylation of aminoglycosides by AAC(6’)-Ib in vitro and completely prevent the growth of A. baumannii A155. Compound 1 was found to be uncompetitive with respect to acetyl-CoA and mixed with respect to the aminoglycoside. The inhibitors identified in this study represent powerful augmentation options with aminoglycosides to combat infections caused by resistant Gram-negative bacteria.
|Advisor:||Tolmasky, Marcelo E.|
|Commitee:||Johnson, Hope A., Rasche, Madeline E.|
|School:||California State University, Fullerton|
|School Location:||United States -- California|
|Source:||MAI 56/06M(E), Masters Abstracts International|
|Subjects:||Biology, Microbiology, Pharmacology, Biochemistry|
|Keywords:||Acinetobacter, Aminoglycoside, Antibiotic resistance, Klebsiella|
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