DESCRIPTION: Antibiotic resistance is currently one of the most significant public health concerns. The World Health Organization recently identified antimicrobial resistance as one of the three greatest threats facing mankind in the 21st century. Cationic host-defense peptides (HDPs) are small cationic amphiphilic peptides, and are an ancient and vital part of the innate immune system. HDPs play an essential role in the defense against bacterial infections, as they have broad-spectrum activity against both Gram-positive and Gram-negative bacteria. In addition, HDPs may have less probability to develop drug-resistance observed for conventional antibiotic treatment due to the novel mechanism of bacterial membrane disruption. As such, HDPs are potential antibiotics due to their antibacterial function. However, HDPs have significant drawbacks such as susceptibility to enzymatic degradation, low-to-moderate activity and their inconvenient optimization. We have recently developed a new class of sequence-specific peptidomimetics termed a-AApeptides. In addition to their intrinsic advantages including enhanced stability against proteolysis and limitless potential for chemical modification, some potent molecules display broad-spectrum antimicrobial activity, and do not induce apparent resistance in drug-resistant pathogens. Furthermore, they can also modulate immune responses and show strong anti-inflammatory activity. In addition, one lead compound has shown potent in vivo activity against MRSA in mouse model. Our preliminary data suggest that antimicrobial a-AApeptides mimic the global structure, function and mechanism of AMPs. These findings strongly suggest a-AApeptides may be a new approach for antibiotic development. Our long-term goal is to develop a new class of antimicrobial peptidomimetics (cyclic-lipidated a-AApeptides) with novel mechanisms in the treatment of bacterial infectious disease. The objective here is to synthesize, develop and evaluation of more potent analogs of previously designed antimicrobial cyclic-lipidated a-AApeptides. We will first design and synthesize novel analogs of previously designed antimicrobial cyclic-lipidated a-AApeptides. Through structure-function-relationship (SFR) studies, we will identify lead cyclic-lipidated a-AApeptides that have potent and broad-spectrum activity against a panel of clinically- relevant Gram-negative and Gram-positive bacteria. We will then investigate if bacterial membrane disruption is the general bactericidal mechanism of lead cyclic-lipidated a-AApeptides. Finally, we will assess their in vivo efficacy in a mouse model. The work proposed in the aims is significant because it leads to the identification of new class of antibiotics combating emergent antibiotic resistance. The work is innovative because these a-AApeptides resemble the defense mechanisms of HDPs, and have potent broad-spectrum activity. They are amendable for development of a generation of antibiotics with novel mechanisms.