COBRE Center for Antimicrobial Resistance and Therapeutic Discovery
The Miriam Hospital

Projects

cobreProject 1

Staphylococcus aureus is a gram-positive bacterium that is clinically prominent with new isolates emerging that exhibit drug resistance, making treatments challenging with the current drug arsenal. S. aureus is the most commonly recognized multi-drug resistant (MDR) pathogen and it often referred to as a “superbug”; methicillin-resistant S. aureus (MRSA) being the most prominent. MRSA is no longer limited to medical hospitals and is rapidly transmitted from person to person. With the growing problem, there is concern about effective treatment, leading to a fervent need for new antimicrobials.

Our examination includes a survey of clinical isolates and low-dose exposure to these compounds. Our aims are as follows:

  • Aim 1: To determine if bacteria have available resistance mechanisms, or if they can develop resistance.
  • Aim 2: To investigate the translation of TrxR targeted compounds to mammalian systems using mice as an infection model for S. aureus, and to determine the drug efficacy of our TrxR targeted compounds on S. aureus inhibition, evaluating systemic and local infections.
  • Aim 3: To build a new class of thioredoxin system inhibitory antibiotics. We will engage an antibacterial target specific screen to identify new compounds, which will enhance our chances of finding a drugable compound. This will drive the investigation of auranofin, shikonin, and other TrxR inhibitory compounds toward use as a treatment option for specific bacterial infections.

PI: Beth Burgwyn Fuchs, PhD

Project 2

Neutrophil Integrins in Defense against Drug-Resistant C. albicans

Systemic candidiasis continues to be a significant medical problem in critically ill patients with high morbidity and mortality, compounded by the emergence of drug-resistant Candida.  Given that both drug-sensitive and drug-resistant forms of Candida must avoid immune clearance to cause persistent infection, restoration of protective immunity would be of broad benefit to the medical management of candidiasis. 

In his research project, Dr. LeBlanc will investigate the roles for the β1 and β2 integrins in mediating human neutrophils interaction with C. albicans, both in vitro and in vivo.  He will also establish whether clinical isolates of drug-resistant C. albicans are differentially susceptible to anti-hyphal host defense when studied in the context of extracellular matrix, and utilize purified fungal cell wall components that modulate integrin signaling to enhance host defenses against fungal infections. Dr. LeBlanc, therefore, adds the host component to combating drug-resistance with a focus on neutrophil effector functions and the drug-resistant fungal pathogen C. albicans.

PI: Brian W LeBlanc, PhD

Project 3

The development and spread of antibiotic resistance is jeopardizing the efficacy of our current antibiotic arsenal. To formulate targeted therapies that make better use of existing antibiotics and reduce the development of resistance, we must understand how antibiotics impact both the pathogenic and beneficial members of the human microbiome. This is particularly important because the disruption of microbiome homeostasis by antibiotics is associated with multiple microbiome-related diseases, such as C. difficile-associated diarrhea and inflammatory bowel disease. Current descriptive microbiome research, focused on identifying taxonomic changes, has not addressed the mechanistic question of why specific bacteria within a microbial community are negatively impacted by antibiotics while others are not. The work proposed here will move past this limitation by transcriptionally profiling the impacts of antibiotics on the total microbial community in vivo to provide functional and mechanistic insight into the action of antibiotics in the microbiome. The central hypothesis of this study is that the induction of tolerance and resistance mechanisms mediates toxicity to antibiotic exposure in susceptible members of the microbiome. This proposal is focused on tolerance mechanisms related to the metabolic state of bacteria before and during treatment. The microbiome consists of many metabolic microenvironments and within these communities metabolically active bacteria are likely to be more susceptible than less active species. Total transcriptional profiles of the microbiome can be used to study the roles of well- defined tolerance and resistance mechanisms within the microbiome in vivo. This project will test our central hypothesis in three aims:

  • Aim 1: Determine the impacts of broad-spectrum antibiotics on the structure of the salivary microbiome derived from clinical samples.
  • Aim 2: Determine the total transcriptional response of the microbiome to bactericidal and bacteriostatic antibiotic therapy.
  • Aim 3: Profile the impacts of ciprofloxacin on the structure and function of the murine microbiome in conjunction with host metabolic perturbation.

In addition to testing this hypothesis, a key goal of this exploratory proposal is to implement a novel outpatient-based methodology to study the response of the human microbiome to antibiotic therapy. The ultimate goal of this work is to provide information about the impact of antibiotic therapy on the structure and function of the microbiome, in order to allow clinicians to select therapies that minimize microbiome-related complications and the transfer and development of resistance. This basic knowledge will help clinicians to improve antibiotic therapy by promoting evidence-based, targeted treatments to safeguard our current arsenal of antibiotics.

PI: Peter A Belenky, PhD

Learn more about the COBRE Center for Antimicrobial Resistance and Therapeutic Discovery (CARTD)