Antibiotic resistance occurs when bacteria adapt to withstand the effects of antibiotics due to overexposure, and over 2 million individuals are infected with antibiotic resistant bacteria each year. Aminoglycosides (AGs) are a class of antibiotic used to treat infections caused by gram-negative bacteria, such as tuberculosis. AGs fight bacterial infections by binding to the A-site of ribosomes and altering their structure, which disrupts protein synthesis and eventually leads to cell death. Bacteria have adapted to combat the mechanism of AGs by modifying the chemical structure of the antibiotic using aminoglycoside modifying enzymes (AMEs). This modification prevents the antibiotic from successfully binding to bacterial ribosomes, and allows the bacteria to proliferate. AAC(6’)-Ib is the most abundant type of AME, and it modifies the structure of AGs by adding an acetyl group to the antibiotic at the 6’ position. Based on computational docking studies using AutoDock Vina, our goal is to synthesize potential small molecule inhibitors of AAC(6’)-Ib. We have developed and optimized the synthetic route for<b> </b>our lead, which involves the synthesis and combination of two small molecule fragments. If successful, potent inhibitors would be used as an adjuvant therapy, taken alongside current AGs and would modify and prevent AAC(6’)-Ib from altering the structure of AGs.

Synthesis of AAC(6’)-Ib inhibitors to combat bacterial resistance to aminoglycosides

255th National Meeting (2018)

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