Christopher J. Kristich, PhD
Professor; Director, Center for Infectious Disease Research
- Translational and Biomedical Research Center
Bacteria are remarkably adaptable. They detect a wide variety of physical and chemical signals in their environment (such as antibiotics), and use that information as regulatory input to control their behavior and physiology (such as antibiotic resistance) – 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 (the input), (2) how these signaling systems control cellular processes in response to environmental conditions (signal processing); and (3) the biochemical mechanisms of antimicrobial resistance and gut colonization (the output). 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.
Enterococci (in particular, Enterococcus faecalis and Enterococcus faecium) are Gram-positive bacteria that are inhabitants of the intestinal tract of everything from insects to humans. Despite this, association of enterococci with humans is not always benign – for the last ~30 years, enterococci have been (and remain today) among the three most common causes of hospital-acquired infections. The success of enterococci as significant hospital-acquired pathogens is, at least in part, a consequence of their remarkable intrinsic resistance to an impressive variety of toxic antimicrobial agents, including widely used antibiotics. Intrinsic resistance of enterococci 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 enterococci to broad-spectrum cephalosporin antibiotics, which prevent bacterial cell-wall crosslinking in susceptible bacteria, enables enterococci 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, the genetic and biochemical basis of enterococcal resistance to cephalosporins and other cell-envelope stresses remains poorly understood. Our research addresses this problem.
We have identified signal transduction pathways in enterococci that are required for intrinsic resistance to various cell-envelope-active antimicrobials, including bile and cephalosporin antibiotics. Thus, these signaling systems are critical for the success of enterococci 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 enterococci, including counterselectable markers, tools 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.
Figure 1. Scanning-electron micrographs of E. faecalis grown with cell-envelope stress. (A) Wild-type E. faecalis cells are intact and exhibit typical enterococcal morphology, indicating they are fully capable of withstanding the imposed envelope stress. (B,C) Mutant E. faecalis cells with defects in a key signal transduction system often exhibit severe morphological defects, including collapsed cells (B) or abnormally elongated and bloated cells (C), indicating that their ability to withstand envelope stress is compromised.
(Labbe BD, Hall CL, Kellogg SL, Chen Y, Koehn O, Pickrum AM, Mirza SP, Kristich CJ.) J Bacteriol. 2019 May 15;201(10) PMID: 30858297 PMCID: PMC6482931 SCOPUS ID: 2-s2.0-85065131964 03/13/2019
(Banla LI, Pickrum AM, Hayward M, Kristich CJ, Salzman NH.) Infect Immun. 2019 03;87(5) PMID: 30804098 PMCID: PMC6479037 SCOPUS ID: 2-s2.0-85065021405 02/26/2019
(Banla LI, Salzman NH, Kristich CJ.) Curr Opin Microbiol. 2019 02;47:26-31 PMID: 30439685 PMCID: PMC6511500 SCOPUS ID: 2-s2.0-85056238106 11/16/2018
(Chakraborty R, Lam V, Kommineni S, Stromich J, Hayward M, Kristich CJ, Salzman NH.) Infect Immun. 2018 12;86(12) PMID: 30224553 PMCID: PMC6246901 SCOPUS ID: 2-s2.0-85056802367 09/19/2018
(Kirkpatrick CL, Parsley NC, Bartges TE, Wing CE, Kommineni S, Kristich CJ, Salzman NH, Patrie SM, Hicks LM.) Microb Biotechnol. 2018 09;11(5):943-951 PMID: 30014612 PMCID: PMC6116741 SCOPUS ID: 2-s2.0-85050586641 07/18/2018
(Kellogg SL, Kristich CJ.) J Bacteriol. 2018 06 15;200(12) PMID: 29632091 PMCID: PMC5971478 SCOPUS ID: 2-s2.0-85047458915 04/11/2018
(Banla IL, Kommineni S, Hayward M, Rodrigues M, Palmer KL, Salzman NH, Kristich CJ.) Infect Immun. 2018 01;86(1) PMID: 29038125 PMCID: PMC5736811 SCOPUS ID: 2-s2.0-85039561569 10/19/2017
(Djorić D, Kristich CJ.) J Bacteriol. 2017 Dec 01;199(23) PMID: 28874409 PMCID: PMC5686589 SCOPUS ID: 2-s2.0-85032975375 09/07/2017
(Labbe BD, Kristich CJ.) J Bacteriol. 2017 11 01;199(21) PMID: 28808126 PMCID: PMC5626955 SCOPUS ID: 2-s2.0-85030528788 08/16/2017
(Hall CL, Lytle BL, Jensen D, Hoff JS, Peterson FC, Volkman BF, Kristich CJ.) J Mol Biol. 2017 07 21;429(15):2324-2336 PMID: 28551334 PMCID: PMC5527686 SCOPUS ID: 2-s2.0-85020666072 05/30/2017
(Kellogg SL, Little JL, Hoff JS, Kristich CJ.) Antimicrob Agents Chemother. 2017 05;61(5) PMID: 28223383 PMCID: PMC5404561 SCOPUS ID: 2-s2.0-85018165537 02/23/2017
(Kommineni S, Kristich CJ, Salzman NH.) Gut Microbes. 2016 11;7(6):512-517 PMID: 27624536 PMCID: PMC5153615 SCOPUS ID: 2-s2.0-84989252479 11/03/2016