Pathogens

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Project Description:

Bacterial resistance to antimicrobial drugs has the potential to become a global health crisis. This problem has necessitated an explosion of research to discover new drug targets as well as synthetic antibiotics. While this tactic is essential to stay ahead of the evolution of antibiotic resistant organisms, it is also important to combat the resistance process. Bacteria can acquire resistance to antibiotics through chromosomal mutations and high rates of resistance-conferring chromosomal mutations are at least partially due to pathways induced to repair damaged DNA caused either directly or indirectly by the antibiotic. In many bacteria the entire response is controlled by a single repressor protein, LexA. The first step of this DNA damage response is the binding of the RecA recombinase protein to DNA, facilitating the inactivation of LexA. This project is designed to identify peptides that bind RecA protein filaments, blocking the LexA binding site. Unlike other antimicrobial peptides currently being studied, we are looking for peptides that reduce the mutability of bacteria as opposed to killing the bacteria. Once identified, these peptides could potentially serve as antibiotic additives and could be used to reduce the evolution rate of bacteria regardless of the molecular target of the drug. The aims of this pilot project include designing short peptides based on the structure of the likely LexA binding site on the RecA protein, screening the effects of the peptides on the LexA cleavage reaction in vitro, and determining the mutation rate of various species of bacteria in the presence of candidate peptides. The goals of this proposal are centered around the hypothesis that inhibition of bacterial RecA-mediated LexA repressor protein cleavage can reduce the acquisition of antibiotic resistance.