The World Health Organization classifies antibiotic resistance as one of the three greatest threats to human health, and efforts aimed at combating antibiotic resistance are essential for the long-term viability of human- kind. Aminoglycosides (AGs) constitute one class of FDA-approved antibiotics that are indicated for severe in- fections caused by Gram-positive and Gram-negative microorganisms, many times in combination with cell- wall active agents. However, resistance to AGs is becoming a major problem, and has rendered several mem- bers of the class obsolete. Resistance to AGs has been partially attenuated by the development of new agents; however, resistance to AGs is still commonly encountered clinically. Therefore, new strategies to overcome antibiotic resistance to AGs remain critical to human health. The broad goal of the present proposal aims to develop agents that circumvent resistance to AG antibiotics. Specifically, the research aims to conduct initial studies toward the development of natural product-based re- sistance-modifying agents (RMAs) for AGs. Studies will be conducted to optimize bacterial potency and host toxicity, and to identify the bacterial target of the natural products. In parallel efforts, additional chemical leads that circumvent AG resistance in MRSA will be sought using a high-throughput screen. Finally, the spectrum of activity of select RMAs will be explored in a variety of microorganisms and in combination with a variety of FDA-approved AG antibiotics.
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