Antibiotic-resistant Gram-positive bacteria, such as Enterococcus faecalis and Staphylococcus aureus, are major causes of hospital-acquired infections. E. faecalis is a successful hospital-acquired pathogen partly due to its intrinsic resistance to commonly used antibiotics that target bacterial cell envelope biogenesis. However, many questions regarding the genetic and biochemical basis for intrinsic antimicrobial resistance in E. faecalis remain unanswered. Preliminary studies identified a new signal transduction system containing a eukaryotic-type Ser/Thr kinase (PrkC) that is required for intrinsic antimicrobial resistance in E. faecalis. We hypothesize that PrkC monitors the cell envelope for perturbations caused by envelope-active antibiotics and mediates an adaptive biological response to produce antimicrobial resistance. Our long-term goal is to understand the role of this new signaling system in mediating resistance, and more generally, the genetic and biochemical basis for intrinsic antimicrobial resistance in E. faecalis. The objective of this proposal is to begin to elucidate the role of signal transduction, and specifically of the PrkC pathway, in mediating intrinsic antimicrobial resistance in enterococci. To achieve this goal, we will: 1) Define the PrkC-dependent regulatory circuit;2) Identify direct substrates for phosphorylation by PrkC;and 3) Characterize effectors of intrinsic antimicrobial resistance (the output of PrkC-dependent signaling). Thus, the research proposed here will provide insights into the function of a new bacterial signaling system, enhance fundamental understanding of the mechanisms responsible for antimicrobial resistance in Gram- positive bacteria, and form the foundation for future efforts to develop innovative therapies against infections caused by resistant bacteria.
Antibiotic-resistant bacteria, such as Enterococcus faecalis and Staphylococcus aureus, are major causes of hospital-acquired infections. The research proposed here will enhance fundamental understanding of the mechanisms responsible for antimicrobial resistance in Gram-positive bacteria and form the foundation for future efforts to develop innovative therapies against infections caused by resistant bacteria.
|Kellogg, Stephanie L; Kristich, Christopher J (2016) Functional Dissection of the CroRS Two-Component System Required for Resistance to Cell Wall Stressors in Enterococcus faecalis. J Bacteriol 198:1326-36|
|Hoff, Jessica S; Kristich, Christopher J (2016) Thymidylate Limitation Potentiates Cephalosporin Activity toward Enterococci via an Exopolysaccharide-Based Mechanism. ACS Chem Biol 11:1561-8|
|Kommineni, Sushma; Bretl, Daniel J; Lam, Vy et al. (2015) Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526:719-22|
|DjoriÄ‡, DuÅ¡anka; Kristich, Christopher J (2015) Oxidative stress enhances cephalosporin resistance of Enterococcus faecalis through activation of a two-component signaling system. Antimicrob Agents Chemother 59:159-69|
|Kristich, Christopher J; DjoriÄ‡, Dusanka; Little, Jaime L (2014) Genetic basis for vancomycin-enhanced cephalosporin susceptibility in vancomycin-resistant enterococci revealed using counterselection with dominant-negative thymidylate synthase. Antimicrob Agents Chemother 58:1556-64|
|Snyder, Holly; Kellogg, Stephanie L; Skarda, Laura M et al. (2014) Nutritional control of antibiotic resistance via an interface between the phosphotransferase system and a two-component signaling system. Antimicrob Agents Chemother 58:957-65|
|Vesic, Dusanka; Kristich, Christopher J (2013) A Rex family transcriptional repressor influences H2O2 accumulation by Enterococcus faecalis. J Bacteriol 195:1815-24|
|Hall, Cherisse L; Tschannen, Michael; Worthey, Elizabeth A et al. (2013) IreB, a Ser/Thr kinase substrate, influences antimicrobial resistance in Enterococcus faecalis. Antimicrob Agents Chemother 57:6179-86|
|Vesic, Dusanka; Kristich, Christopher J (2012) MurAA is required for intrinsic cephalosporin resistance of Enterococcus faecalis. Antimicrob Agents Chemother 56:2443-51|
|Kristich, Christopher J; Little, Jaime L (2012) Mutations in the Ã½Ã½ subunit of RNA polymerase alter intrinsic cephalosporin resistance in Enterococci. Antimicrob Agents Chemother 56:2022-7|
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