Novel Lantibiotic Against C. diff Infections May Improve Lipid Profile

MedicalResearch.com Interview with:

Rajesh Kumar NV, Ph.D.Affiliation during the study:Senior Manager, Human Therapeutics Division,Intrexon Corporation, Germantown, MD, USA

Dr. Rajesh Kumar NV

Rajesh Kumar NV, Ph.D.
Affiliation during the study:
Senior Manager, Human Therapeutics Division,
Intrexon Corporation, Germantown, MD, USA
Current affiliation:
Translational Research Program Manager, Oncology Drug Discovery,
Department of Radiation Oncology and Molecular Radiation Sciences,
Johns Hopkins University School of Medicine
Baltimore, MD,  


MedicalResearch.com: What is the background for this study?

Response: Clostridium difficile is a bacterium that can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon. Clostridium difficile infection is the most frequent form of colitis in hospitals and nursing homes and affects millions of patients in the United States and abroad. Clostridium difficile associated disease (CDAD) is a global public health challenge where even mild to moderate infections at times can quickly progress to a fatal disease if not treated promptly.

OG253 is a novel lantibiotic in development for the treatment of CDAD. Lantibiotics are antimicrobial peptides whose chemical structure includes a bridge maintained by the non-canonical amino acid lanthionine. The primary objective of our study was to evaluate the repeated dose toxicokinetics and any possible side effects of OG253 as enteric-coated capsules following daily oral administrations of three different doses (6.75, 27 and 108 mg/day) for a single day or seven consecutive days in both genders of rats.

An enteric-coated capsule of OG253 was formulated in an attempt to circumvent the proteolytic degradation of OG253 in the upper digestive tract and specifically deliver this lantibiotic to the distal portion of the small intestine.

MedicalResearch.com: What are the main findings? 

Response: Our results suggest that all three doses of OG253 was generally well tolerated and did not lead to adverse events, alterations in body weight or food consumption in both one-day acute tolerability and seven-day repeated dose studies. OG253 capsule administration neither significantly alter the weight of organs nor affect the hematology, coagulation, clinical biochemistry parameters compared to placebo capsule administered animals.

Unexpectedly, our preclinical study revealed that OG253 treatment results in significantly greater reduction in serum cholesterol and triglyceride levels than placebo capsules in both genders of rats. The greatest reduction in cholesterol (29.8 %) and triglyceride (61.38 %) was observed with 108 mg/day dose of OG253 for seven consecutive days.

MedicalResearch.com: What should readers take away from your report? 

Response: With the rise in antibiotic resistance, there is a desperate need for new antimicrobials, especially those with a new mechanism of action. Our work suggests that lantibiotics are an attractive class of new molecules that have a good safety profile. The potential effect of these compounds on cholesterol and triglyceride levels does not raise safety concerns, yet warrants further investigation. Our findings highlights that short-term treatment with lantibiotics may have potential utility as cholesterol and triglyceride lowering agents. 

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: There are limitations to our study. The study findings were based on data from a relatively small number of animals. A study of this size and duration cannot rule out side effects that might emerge after a longer period of observation. Additional research is required to determine the safety profile of OG253 under longer exposure. 

Citation:

Rajeshkumar NV, Kers JA, Moncrief S, Defusco AW, Park JH, Handfield M. Preclinical evaluation of the maximum tolerated dose and toxicokinetics of enteric-coated lantibiotic OG253 capsules. Toxicology and Applied Pharmacology, Volume 374, 1 July 2019, Pages 32-40

https://www.ncbi.nlm.nih.gov/pubmed/31034929

May 9, 2019 @ 5:43 pm

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