A MraY inhibitor from a natural source, capuramycin, exhibited significant activity in vivo using M. tuberculosis mouse infection model. Muraymycins possess a common core structure of capuramycin, however, their structural diversity is observed in an acyclic complex depsipeptide moiety and the C5'-sugar-appended. Promising in vivo antibactericidal activity of muraymycin A1 against S. aureus was highlighted by the Wyeth-Research groups. Thus, it is of our interest to validate the efficacy of muraymycin A1 in vitro and in vivo against M. tuberculosis. However, the fungus strain (Streptomyces spp. LL-AA896) used to produce muraymycin A1 and any congeners are not available, and muraymycin A1 has to be synthesized for the in vitro compound profiling. Thus, we will establish the synthetic route for intact muraymycin A1 to obtain enough molecules (Specific Aim 1). Furthermore, medicinal chemistry programs of muraymycin A1 and capuramycin with an aim to improve the efficacy including pharmacokinetics are hampered by 1) the complexity of these structures, 2) difficulty in chemically modifying the desired positions selectively, and 3) no convenient assay against Mtb MraY enzyme including difficulty in obtaining enough MraY substrate, Park's nucleotide. We accomplished a scalable chemoenzymatic and total synthesis of Park's nucleotide and its fluorescent probe, and established a convenient MraY inhibitor assay using a cell envelop enriched fraction including MraY, MurG and decaprenylphosphate. In addition, over the past years we obtained extensive knowledge of synthetic accessibility of uridine-amino-alcohol containing molecules in solution or on the polymer- support. We will continue designing and synthesizing new uridine-amino-alcohol derivatives in order to identify the minimal and essential structures of muraymycins and capuramycin (Specific Aim 2). In vitro profiling of the generated molecules against Mtb MraY and drug-sensitive and -resistant M. tuberculosis will be performed at the CSU Mycobacteria Research Laboratory (Specific Aim 3).
Multidrug resistant Mycobacterium tuberculosis (MDR-TB) has occurred in hospitals and correctional facilities, and frequently in HIV-infected patient. Clinical responses of MDR- TB patient to currently available drugs have been poor, and in some cases there is no response at all. The long term goal of this grant submission is to develop new drug leads for MDR-TB.
|Siricilla, Shajila; Mitachi, Katsuhiko; Yang, Junshu et al. (2017) A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii. J Med Chem 60:2869-2878|
|Mitachi, Katsuhiko; Siricilla, Shajila; Yang, Dong et al. (2016) Fluorescence-based assay for polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA) and identification of novel antimycobacterial WecA inhibitors. Anal Biochem 512:78-90|
|Mitachi, Katsuhiko; Aleiwi, Bilal A; Schneider, Christopher M et al. (2016) Stereocontrolled Total Synthesis of Muraymycin D1 Having a Dual Mode of Action against Mycobacterium tuberculosis. J Am Chem Soc 138:12975-12980|
|Mitachi, Katsuhiko; Kurosu, Yuki E; Hazlett, Brandon T et al. (2016) Oxyma-based phosphates for racemization-free peptide segment couplings. J Pept Sci 22:186-91|
|Mitachi, Katsuhiko; Sharma Gautam, Lekh Nath; Rice, Jeffrey H et al. (2016) Structure determination of lipopeptides from Mycobacterium avium subspecies paratuberculosis and identification of antigenic lipopeptide probes. Anal Biochem 505:29-35|
|Siricilla, Shajila; Mitachi, Katsuhiko; Wan, Bajoie et al. (2015) Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. J Antibiot (Tokyo) 68:271-8|
|Mitachi, Katsuhiko; Siricilla, Shajila; Klaic, Lada et al. (2015) Chemoenzymatic syntheses of water-soluble lipid I fluorescent probes. Tetrahedron Lett 56:3441-3446|
|Mitachi, Katsuhiko; Mohan, Priya; Siricilla, Shajila et al. (2014) One-pot protection-glycosylation reactions for synthesis of lipid?II analogues. Chemistry 20:4554-8|
|Siricilla, Shajila; Mitachi, Katsuhiko; Skorupinska-Tudek, Karolina et al. (2014) Biosynthesis of a water-soluble lipid I analogue and a convenient assay for translocase I. Anal Biochem 461:36-45|
|Wang, Yong; Siricilla, Shajila; Aleiwi, Bilal A et al. (2013) Improved synthesis of capuramycin and its analogues. Chemistry 19:13847-58|
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