Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE.
The emergence of extensively drug-resistant tuberculosis (XDR-TB) necessitates the need to identify new anti-tuberculosis drug targets as well as to better understand essential biosynthetic pathways. GlgE is a Mycobacterium tuberculosis (Mtb) encoded maltosyltransferase involved in α-glucan biosynthesis. Deletion of GlgE in Mtb results in the accumulation of M1P within cells leading to rapid death of the organism. To inhibit GlgE a maltose-C-phosphonate (MCP) 13 was designed to act as an isosteric non-hydrolysable mimic of M1P. MCP 13, the only known inhibitor of Mtb GlgE, was successfully synthesized using a Wittig olefination as a key step in transforming maltose to the desired product. MCP 13 inhibited Mtb GlgE with an IC₅₀=230 ± 24 μM determined using a coupled enzyme assay which measures orthophosphate release. The requirement of M1P for the assay necessitated the development of an expedited synthetic route to M1P from an intermediate used in the MCP 13 synthesis. In conclusion, we designed a substrate analogue of M1P that is the first to exhibit Mtb GlgE inhibition.
Department of Chemistry, The University of Toledo, 2801 W. Bancroft Street, MS602, Toledo, OH 43606, United States.
Sri Kumar
SK
Veleti
Department of Chemistry, The University of Toledo, 2801 W. Bancroft Street, MS602, Toledo, OH 43606, United States.
Jared J
JJ
Lindenberger
Department of Chemistry, The University of Toledo, 2801 W. Bancroft Street, MS602, Toledo, OH 43606, United States.
Donald R
DR
Ronning
Department of Chemistry, The University of Toledo, 2801 W. Bancroft Street, MS602, Toledo, OH 43606, United States. Electronic address: steve.sucheck@utoledo.edu.
Steven J
SJ
Sucheck
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005936:Glucans / Q000096:biosynthesis; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008320:Maltose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010757:Phosphorous Acids / Q000737:chemistry*; D013403:Sugar Phosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005936:Glucans; D063065:Organophosphonates; D010757:Phosphorous Acids; D013403:Sugar Phosphates; C000591911:maltose C-phosphonate; C570063:phosphonic acid; C080751:maltose 1-phosphate; D008320:Maltose; D005964:Glucosyltransferases; C436710:maltosyltransferase
C-phosphonates; Enzyme inhibition; GlgE; Maltose-1-phosphate; Mycobacterium tuberculosis