Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase Journal Article
| Authors: | Bryk, R.; Arango, N.; Maksymiuk, C.; Balakrishnan, A.; Wu, Y. T.; Wong, C. H.; Masquelin, T.; Hipskind, P.; Lima, C. D.; Nathan, C. |
| Article Title: | Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase |
| Abstract: | Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD+/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors. © 2013 American Chemical Society. |
| Keywords: | genetics; mutant protein; metabolism; high throughput screening; drug effect; drug screening; enzymology; enzyme inhibitor; molecular library; drug evaluation, preclinical; small molecule libraries; high-throughput screening assays; structure activity relation; structure-activity relationship; bacterial protein; chemistry; drug antagonism; mycobacterium tuberculosis; bacterial proteins; enzyme inhibitors; sulfonamide; sulfonamides; recombinant proteins; recombinant protein; cell membrane; drug derivative; binding site; binding sites; mutant proteins; conformation; molecular conformation; biological transport; arginine; cell membrane permeability; dihydrolipoamide dehydrogenase; antitubercular agents; thioctic acid; transport at the cellular level; microbial sensitivity tests; tuberculostatic agent; humans; human; article; 2 (2 amino 5 bromo n methylpyridine 3 sulfonamido) n (4 methoxyphenyl)acetamide; 2-(2-amino-5-bromo-n-methylpyridine-3-sulfonamido)-n-(4-methoxyphenyl)acetamide; agents affecting water, molecule or ion transport; benzeneacetamide derivative; thioctamide; microbial sensitivity test; benzeneacetamides; membrane transport modulators |
| Journal Title: | Biochemistry |
| Volume: | 52 |
| Issue: | 51 |
| ISSN: | 0006-2960 |
| Publisher: | American Chemical Society |
| Date Published: | 2013-12-23 |
| Start Page: | 9375 |
| End Page: | 9384 |
| Language: | English |
| DOI: | 10.1021/bi401077f |
| PUBMED: | 24251446 |
| PROVIDER: | scopus |
| PMCID: | PMC3894633 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):1 -- Export Date: 2 April 2014 -- CODEN: BICHA -- Source: Scopus |
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