Pathogens

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Research Description:

Antibiotic resistance is a global healthcare crisis requiring new tools to combat bacterial, fungal and parasitic infections. Effective therapies exist for many infections, but it is well understood that the use of antibiotics has led to a growing number of pathogens with resistance to commonly available and inexpensive drugs. There is an urgent need to discover or develop new antibiotics to treat resistant infections. Continued existence of this need represents an important problem because unless dealt with, costs of antibiotic resistance -- economic and human -- will continue to mount. We use a novel approach to antimicrobial discovery, by combining specific functional parts of naturally occurring immune molecules called antimicrobial peptides (AMPs) to form new molecules. Our long-term goal is to develop potent novel antibiotics from natural AMPs to effectively treat infections with increased target specificity, while retaining key attributes of the native synthetic AMPs by combining specific functional structures from AMPs of different organisms in non-natural configurations. Our underlying central hypothesis is that we can easily and inexpensively combine structures from natural AMPs in new combinations to develop hybrid AMPs (hAMPs) to target pathogens at low doses, without damaging host cells. Our rationale is that naturally occurring AMPs are a good basis for new compounds to treat antibiotic-resistant infections. This proposed research is relevant to the INBRE mission of biomedical research with an aim to better treat infectious diseases and the greater NIH mission to advance the nation's capacity to protect and improve health by the prevention and cure of human diseases. We will employ a combination of bioinformatic analyses, molecular biology and protein expression, and antimicrobial activity assays, all geared toward achieving the following specific aims: 1) Design and create novel hybrid AMP genes. The working hypothesis is that gene sequences of existing AMP molecules can be recombined to generate novel chimeric genes to be recombinantly expressed. 2) Characterize the antibacterial activities of hAMPs. The working hypothesis is that novel hAMPs will have antibacterial activities with low MICs compared to the parent molecules, different activitiy spectra to the original AMPs, and low toxicity to eukaryotic cells. Our innovative research could have far-reaching and significant positive impacts: the potential for discovering important alternative antimicrobial drugs; a training ground for minority students in biomedical research; and an opportunity for a small rural university to take part in important cutting-edge research. The proposed investigations would be a springboard for new drug discovery at a time when there is a need for novel therapies because the availability of truly new antibiotics has not kept pace with increasing drug resistance.