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.
authors.affiliation: Department of Microbiology and Immunology and ‡Department of Pharmacology, Weill Cornell Medical College , New York, New York 10065, United States.
authors.forename: Ruslana
authors.initials: R
authors.lastname: Bryk
authors.forename: Nancy
authors.initials: N
authors.lastname: Arango
authors.forename: Christina
authors.initials: C
authors.lastname: Maksymiuk
authors.forename: Anand
authors.initials: A
authors.lastname: Balakrishnan
authors.forename: Ying-Ta
authors.initials: YT
authors.lastname: Wu
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.forename: Thierry
authors.initials: T
authors.lastname: Masquelin
authors.forename: Philip
authors.initials: P
authors.lastname: Hipskind
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lima
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044482:Benzeneacetamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D008058:Dihydrolipoamide Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C586751:2-(2-amino-5-bromo-N-methylpyridine-3-sulfonamido)-N-(4-methoxyphenyl)acetamide; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D044482:Benzeneacetamides; D004791:Enzyme Inhibitors; D049990:Membrane Transport Modulators; D050505:Mutant Proteins; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013449:Sulfonamides; D008063:Thioctic Acid; C013091:lipoamide; D001120:Arginine; D008058:Dihydrolipoamide Dehydrogenase