Inhibition of the futalosine pathway for menaquinone biosynthesis suppresses Chlamydia trachomatis infection.

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2021-12

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Abstract

Chlamydia trachomatis, an obligate intracellular bacterium with limited metabolic capabilities, possesses the futalosine pathway for menaquinone biosynthesis. Futalosine pathway enzymes have promise as narrow-spectrum antibiotic targets, but the activity and essentiality of chlamydial menaquinone biosynthesis have yet to be established. In this work, menaquinone-7 (MK-7) was identified as a C. trachomatis-produced quinone through liquid chromatography-tandem mass spectrometry. An immunofluorescence-based assay revealed that treatment of C. trachomatis-infected HeLa cells with the futalosine pathway inhibitor docosahexaenoic acid (DHA) reduced inclusion number, inclusion size, and infectious progeny. Supplementation with MK-7 nanoparticles rescued the effect of DHA on inclusion number, indicating that the futalosine pathway is a target of DHA in this system. These results open the door for menaquinone biosynthesis inhibitors to be pursued in antichlamydial development.

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10.1002/1873-3468.14223

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Dudiak, Brianne M, Tri M Nguyen, David Needham, Taylor C Outlaw and Dewey G McCafferty (2021). Inhibition of the futalosine pathway for menaquinone biosynthesis suppresses Chlamydia trachomatis infection. FEBS letters, 595(24). pp. 2995–3005. 10.1002/1873-3468.14223 Retrieved from https://hdl.handle.net/10161/24484.

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Scholars@Duke

Needham

David Needham

Professor Emeritus in the Thomas Lord Department of Mechanical Engineering and Materials Science

Professor Needham has been at Duke since 1987 and over the years has developed many collaborative and scholarly relationships across the campus and Medical School. He holds Faculty and membership appointments as: Associate Professor of Biomedical Engineering; Center for Bioinspired Materials and Material Systems; Center for Biomolecular and Tissue Engineering; Duke Comprehensive Cancer Center; and the Duke Cancer Institute.  Internationally, he holds a joint appointment as Professor of Translational Therapeutics in the School of Pharmacy, at the University of Nottingham, UK.  He also collaborates with preclinical researchers at the Erasmus University Medical Center, in Rotterdam, NL. 
For the past 35 years Needham's Lab has developed and used a platform technology of micropipette manipulation to manipulate single and pairs of micro bubbles, droplets and particles in order to assess their behavior in well-defined fluids and solution conditions.  Recently his research and development has focused on nucleation, growth and stability of nanoparticles.  Applications of these fundamental particle and interfacial studies have primarily focused on advanced drug delivery treatments for cancer and now COVID19 with a nasal and throat spray prophylactic and early treatment regimen.

McCafferty

Dewey G. McCafferty

Professor of Chemistry

Our research interests are broadly based in chemical biology, mechanistic enzymology and molecular medicine. Towards this end our group is engaged in understanding the chemical and kinetic mechanisms, substrate specificity and therapeutic importance of enzymes that posttranslationally modify chromatin, such as histone deacetylases, histone demethylases, histone methyl transferases, and chromatin assembly and remodeling complexes. Building on a mechanistic foundation, our laboratory is also interested in the design, chemical synthesis and evaluation of small molecules to modulate the activity of chromatin modifying enzymes within living cells. This work has recently led to the discovery of histone deamethylases as potential targets for anti-depression therapy. In addition, our laboratory also works to identify and develop novel strategies to overcome bacterial resistance to antibiotics through mechanistic characterization of enzymes involved in bacterial virulence, peptidoglycan biosynthesis, and teichoic acid biosynthesis. A central component of this research is the identification of novel anti-virulence chemotherapeutics and antibiotics capable of overcoming infections from antibiotic resistant bacteria. Our group also works to decode the molecular mechanisms of enzymes involved in mechanistically intriguing reactions from antibiotic natural product biosynthesis. Lastly, our group is working to develop a functional view of the molecular underpinning of initial signaling events in bacterial-induced inflammation, and in turn lay the foundation for the discovery and design of novel small molecule inhibitors of Crohn's disease, ulcerative colitis and related inflammatory bowel disorders.


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