INTRINSIC CEPHALOSPORIN RESISTANCE IN ENTEROCOCCI

PROJECT SUMMARYThe continued and inevitable emergence of antibiotic resistance demands a vigorous and sustainedeffort to identify fundamentally new targets and strategies for innovative antimicrobial therapeutics.Antibiotic-resistant enterococci are major causes of hospital-acquired infections. Enterococci aresuccessful hospital-acquired pathogens in part because of their intrinsic resistance to commonly usedantibiotics that target the bacterial cell envelope, such as cephalosporins. However, many questionsremain regarding the genetic and biochemical basis for cephalosporin resistance in enterococci.Previous work revealed a key role for a transmembrane protein kinase (IreK) and its intracellularsubstrate (IreB) in regulation of cephalosporin resistance, but the downstream effectors in the signalingpathway remain unknown. In preliminary studies we showed that one (MurAA) of two UDP-GlcNAc1-carboxyvinyltransferases encoded in E. faecalis (catalyzing the first committed step in peptidoglycanbiosynthesis) is specifically required for cephalosporin resistance. The paralog of MurAA (MurAB)cannot drive cephalosporin resistance. Hence, MurAA possesses a specialized, specific ability topromote cephalosporin resistance. The major knowledge gaps to be addressed are that (i) abiochemical link between the IreK pathway and MurAA has not been established, and (ii) themechanism by which MurAA drives cephalosporin resistance is unknown. The research proposed hereis designed to elucidate new insights into the role of MurAA in the biological processes that driveenterococcal cephalosporin resistance. By doing so, we will provide new insights into the fundamentalbiological processes that drive key antibiotic resistance in enterococci and may define new targets forinnovative therapeutics designed to impair enterococcal cephalosporin resistance.