The Crick laboratory has pursued biochemical studies on the structure and biogenesis of the cell-wall and lipids of Mycobacterium tuberculosis since joining the Mycobacteria Research Laboratories at the Colorado State University Department of Microbiology, Immunology and Pathology. The primary focus of the lab is in the development of enzyme assays and characterization of enzymes and metabolic pathways although we also have experience synthesizing substrates and products for enzymatic reactions and have numerous publications detailing characterization of and development of high throughput screens for many enzymes expressed in M. tuberculosis.
Cell wall synthesis
The laboratory has been among the front runners in establishing the structure and synthesis of mycobacteria cell wall. This has resulted in numerous publications on cell wall structure and novel modifications in these pathogenic bacteria, as well as, identification and characterization of the enzymes responsible for many of these novel features.
Isopentenyl diphosphate synthesis
Isopentenyl diphosphate is as obligate intermediate in the synthesis of all isoprenoid compounds. We have demonstrated that M. tuberculosis utilizes the methylerythritol phosphate (MEP) pathway for synthesis of isopentenyl diphosphate rather than the mevalonate pathway utilized by Homo sapiens and many other eukaryotes. Since the MEP pathway does not exist in man it is generally thought to be a promising drug target and we have cloned, expressed, characterized and evaluated most of the enzymes in the MEP pathway as potential drug targets in M. tuberculosis and other pathogenic bacteria.
The laboratory recently been involved in the study of the function and synthesis of menaquinone in mycobacteria and we were among the first proponents of the pathway as a potential drug target in M. tuberculosis.
Drug target analysis in collaboration with various groups working on diverse antibiotics
Identification of the target of new antimicrobials is critical to understanding mechanism of action as well as designing improved compounds. We have collaborated with a number of groups that are interested in or synthesizing new antimicrobials and provided insight into the mechanism of action of a number of promising inhibitors.
- Composition and Methods of Use of Electron Transport System Inhibitors Serial Number: PCT / US 2007 / 63122. Kurosu, M.; Crick, D. C. US Patent 2007.
- Acid and Base Stable Diphenylmethanol Derivatives and Method of Use. Kurosu, M.; Crick, D. C. US Patent February 2008.
- Combined Anti-Acid-Fast Bacterial Agent, Screening Method for Anti-Acid-Fast Bacterial agents, and Activity Inhibitor of WecA or Ortholog Thereof. Ishizaki, Y.; Igarashi, M.; Brennan, P.J.; Crick, D.C. US Patent December 2017.
Kostenkova K, Arhouma Z, Postal K, Rajan A, Kortz U, Nunes GG, Crick DC, Crans DC.
J Inorg Biochem. 2021 Jan 19;217:111356. doi: 10.1016/j.jinorgbio.2021.111356. Online ahead of print.PMID: 33582396
The Acid-Base Equilibrium of Pyrazinoic Acid Drives the pH Dependence of Pyrazinamide-Induced Mycobacterium tuberculosis Growth Inhibition.
Fontes FL, Peters BJ, Crans DC, Crick DC.
ACS Infect Dis. 2020 Nov 13;6(11):3004-3014. doi: 10.1021/acsinfecdis.0c00507. Epub 2020 Oct 20.PMID: 33078607
Mycobacterium tuberculosis Survival in J774A.1 Cells Is Dependent on MenJ Moonlighting Activity, Not Its Enzymatic Activity.
Kumar S, Koehn JT, Gonzalez-Juarrero M, Crans DC, Crick DC.
ACS Infect Dis. 2020 Oct 9;6(10):2661-2671. doi: 10.1021/acsinfecdis.0c00312. Epub 2020 Sep 16.PMID: 32866371
Pidgeon SE, Apostolos AJ, Nelson JM, Shaku M, Rimal B, Islam MN, Crick DC, Kim SJ, Pavelka MS, Kana BD, Pires MM.
ACS Chem Biol. 2019 Oct 18;14(10):2185-2196. doi: 10.1021/acschembio.9b00427. Epub 2019 Sep 16.PMID: 31487148
Koehn JT, Crick DC, Crans DC.
ACS Omega. 2018 Nov 5;3(11):14889-14901. doi: 10.1021/acsomega.8b02620. eCollection 2018 Nov 30.PMID: 31458155
news and updates
A brand new mass-spectral imaging system built at CSU will help scientists to observe cells in more detail.
As director of the Mycobacteria Research Laboratories Dean Crick explains how cancer research could help tuberculosis.
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Lab: Microbiology Rooms B304, B330