MedicalResearch.com Interview with:
Charles Darkoh, Ph.D., MS., MSc.
University of Texas Health Science Center at Houston
School of Public Health
Department of Epidemiology, Human Genetics & Environmental Sciences
Center for Infectious Diseases
Houston, Texas 77030
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Clostridium difficile (Cdiff) is a multidrug-resistant pathogen that takes over the colon after the good bacteria in the colon have been wiped out by antibiotic therapy. As a result, antibiotic treatment is a major risk factor for C. diff infections. Because of the ability of C. diff to inactivate the majority of the antibiotics currently available, it has become necessary to urgently develop a non-antibiotic therapy for this life-threatening infection. We know that C. diff causes disease by producing toxins, designated toxin A and B. During infection, the toxins are released into the colon resulting in diarrhea and inflammation of the colon as well as other diarrhea-associated illnesses. We also know that C. diff strains that are unable to produce toxins cannot cause disease. Therefore, the toxins are promising targets for a non-antibiotic therapy.
We reported last year that C. difficile regulates toxin production using quorum sensing — a system that allows bacteria to coordinate their biological activities as a group. Two sets of quorum-sensing genes (agr1 and agr2) were identified. These genes form part of a signaling communication system that makes a small peptide, which serves as a cue for the infecting bacterial population to turn on their toxin genes.
In this study we used genetic analysis to identify which of these two sets of genes is responsible for regulating the toxins. Our results demonstrates that agr1 is the culprit. This is because Cdiff agr1 mutant cannot produce toxins and unable to cause disease in mice, whereas the agr2 mutant can cause disease just like the wild type C.diff.
MedicalResearch.com: What should readers take away from your report?
Response: The significance of this study is that the proteins encoded by these genes can directly be inactivated to develop a non-antibiotic therapy for C. diff infections. By crippling their toxin-making machinery, C.diff cannot make toxins and thus cannot cause disease. My laboratory is already working on this and was awarded a 5-year NIH grant to investigate and develop an oral compounds we have identified that inactivate the toxins and block the toxin-making machinery of C.diff by targeting this pathway .
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Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of Clostridium difficile. Charles Darkoh, Chioma Odo, Herbert L. DuPont, doi: 10.1128/mBio.01237-1616 August 2016 mBio vol. 7 no. 4 e01237-16
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