Microbiology and Molecular Genetics

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Christopher J Kristich, PhD

Associate Professor
Microbiology and Molecular Genetics
Medical College of Wisconsin

Research Focus: Signal Transduction and Antibiotic Resistance in Gram-Positive Bacteria

PhD: University of Illinois, Urbana-Champaign (2002)

 

Overview

Bacteria are remarkably adaptable.  They detect a wide variety of physical and chemical signals in their environment, and use that sensory information as regulatory input to control their behavior and physiology – thereby maximizing their ability to survive and proliferate in the face of fluctuating environmental conditions.  We use genetic, molecular, biochemical, and genomic experimental approaches to understand (1) the mechanisms by which Gram-positive bacteria sense internal and external stimuli, and (2) how these signaling systems control cellular processes in response to environmental conditions.  Our goal is to understand all aspects of the sensory process:  to define the signals that are sensed, to understand the signal transduction processes mechanistically, to identify the corresponding physiological or behavioral output, and to elucidate how that output – the product of the signal transduction processes – enhances the ability of the bacteria to survive and proliferate in their natural settings.  Bacterial signal transduction processes play critical roles underpinning the relationship between bacteria and human hosts in both healthy and disease states.  For example, signal transduction mediates adaptation of bacteria to different niches within the host during colonization; influences the transition from benign co-existence to a pathogenic condition; and allows the bacteria to tolerate toxic antimicrobial challenges that would otherwise eradicate them.  Therefore, we approach problems of bacterial signal transduction in the context of basic bacterial physiology, host-microbe interactions, and microbial pathogenesis, with the goal of understanding how fundamental bacterial signaling processes serve to shape the outcome of interactions with human hosts and the environment.

Research Summary

The bacterium Enterococcus faecalis is a Gram-positive member of the normal human intestinal tract.  Despite this, association of enterococci with humans is not always benign – for the last 20 years, enterococci have been (and remain today) among the three most common causes of hospital-acquired infections.  The success of E. faecalis as a significant hospital-acquired pathogen is, at least in part, a consequence of its remarkable intrinsic resistance to an impressive variety of toxic antimicrobial agents, including widely used antibiotics.  Intrinsic resistance of E. faecalis to specific classes of antimicrobials – those that are active against the bacterial cell-envelope – is especially important in the context of hospital-acquired enterococcal infections.  For example, intrinsic resistance to detergents found in the intestinal emulsifying agent, bile, facilitates enterococcal colonization of the intestine, an important first step which usually precedes the onset of hospital-acquired infections.  Furthermore, intrinsic resistance of E. faecalis to broad-spectrum cephalosporin antibiotics, which prevent bacterial cell-wall crosslinking in susceptible bacteria, enables E. faecalis to multiply to abnormally high intestinal cell densities when the ecological balance of the normal intestinal flora is disrupted in patients undergoing cephalosporin therapy – a known risk factor for enterococcal infection.  However, despite the importance of intrinsic antibiotic resistance exhibited by E. faecalis, the genetic and molecular basis of this resistance remains poorly understood.  Our research addresses this problem.

We have identified signal transduction pathways in E. faecalis that are required for its intrinsic resistance to various cell-envelope-active antimicrobials, including bile and cephalosporin antibiotics.  Thus, these signaling systems are critical for the success of E. faecalis as an opportunistic pathogen.  We are using a variety of approaches to probe the functions of these signaling systems at the molecular level, to understand how the systems are integrated with each other to produce the antimicrobial-resistant phenotype, and to determine how these systems promote enterococcal colonization of the intestinal tract and the onset of hospital-acquired infections.  To facilitate our research, we have successfully developed a collection of critical genetic tools that enable efficient genetic analysis of E. faecalis, including counterselectable markers, conjugative delivery systems for allelic exchange, and tools for random and efficient transposon mutagenesis, among others.  Armed with these essential tools, we are well-positioned to make rapid progress on important problems in enterococcal biology, with the long-term goal of developing new strategies for preventing or otherwise treating intractable infections caused by multi-antibiotic-resistant enterococci.
 

 

Scanning-electron micrographs of E. faecalis cultured under conditions in which the cells experience envelope stress.  (A) Wild-type E. faecalis cells are intact and exhibit typical enterococcal morphology, indicating they are fully capable of withstanding the imposed stress.  (B) Mutant E. faecalis cells lacking a key signal transduction protein often exhibit severe morphological defects, such as the loss of envelope integrity that is reflected by the collapsed cell on the right-hand side, indicating that their ability to withstand envelope stress is comprised.

 

Recent Publications

 

Contact Information
Email: ckristich@mcw.edu
Phone: 414-955-4141
Room: TBRC C3930

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Page Updated 06/22/2012