A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Inoyama, Daigo; Awasthi, Divya; Capodagli, Glenn C.; Tsotetsi, Kholiswa; Sukheja, Paridhi; Zimmerman, Matthew; Li, Shao Gang; Jadhav, Ravindra D.; Russo, Riccardo; Wang, Xin; Grady, Courtney; Richmann, Todd; Shrestha, Riju; Li, Liping; Ahn, Yong Mo; Liang, Hsin Pin Ho; Mina, Marizel; Park, Steven; Perlin, David S.; Connell, Nancy; Dartois, Véronique; Alland, David; Neiditch, Matthew B.; Kumar, Pradeep; Freundlich, Joel S.

doi:10.1016/j.chembiol.2020.02.007

Cited by 24 publications

(34 citation statements)

References 65 publications

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“…We unblinded the compound identities to compare their known mechanisms of action to those predicted by MorphEUS. These compounds (DG167 and its derivative JSF-3285) were validated through extensive biophysical, X-ray crystallographic, biochemical binding, and spontaneous drug-resistant mutant studies to be inhibitors of cell wall mycolate biosynthesis through specific engagement of the α-ketoacyl synthase KasA (39,40). Taken together, our analysis of DG167 and JSF-3285 using MorphEUS has independently validated the target pathway of these two compounds and shown these analogs act through the same pathway of action.…”

Section: Morpheus Correctly Classifies Cellular Targets Of Unknown Drmentioning

confidence: 79%

Morphological profiling of tubercle bacilli identifies drug pathways of action

Smith

Pullen

Olson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here we utilized the cell-to-cell variation in morphological features of Mycobacterium tuberculosis bacilli to develop a rapid profiling platform called Morphological Evaluation and Understanding of Stress (MorphEUS). MorphEUS classified 94% of tested drugs correctly into broad categories according to modes of action previously identified in the literature. In the other 6%, MorphEUS pointed to key off-target activities. We observed cell wall damage induced by bedaquiline and moxifloxacin through secondary effects downstream from their main target pathways. We implemented MorphEUS to correctly classify three compounds in a blinded study and identified an off-target effect for one compound that was not readily apparent in previous studies. We anticipate that the ability of MorphEUS to rapidly identify pathways of drug action and the proximal cause of cellular damage in tubercle bacilli will make it applicable to other pathogens and cell types where morphological responses are subtle and heterogeneous.

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Section: Morpheus Correctly Classifies Cellular Targets Of Unknown Drmentioning

confidence: 79%

Morphological profiling of tubercle bacilli identifies drug pathways of action

Smith

Pullen

Olson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…As necessary, reactions were performed under a nitrogen atmosphere with anhydrous solvents. Instrumentation and analytical pipelines for testing of the synthesized compounds were as previously described [37,52]. In sum, an Avance 500 MHz spectrometer from BrukerAU : PerPLOSstyle; CorporationorCorp:isnotallow was used for determination of NMR spectra of the synthesized compounds.…”

Section: Compound Synthesismentioning

confidence: 99%

Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs

et al. 2021

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Sensing and response to environmental cues, such as pH and chloride (Cl−), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl− levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure–activity relationship studies on the hit compound “C6,” or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl− response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl− response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl−-responsive genes in the simultaneous presence of cholesterol and high external Cl− concentration, versus transcript levels observed during exposure to high external Cl− concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.

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“…The enzymes KasA and KasB, two components of the FAS-II pathway, function in tandem to carry out acyl chain elongation to achieve meromycolic acids from acyl primers provided by FAS-I. In particular, KasA has been shown to sustain the virulence and persistence of Mtb in vivo, thus representing an ideal candidate for medicinal chemistry efforts [51]. In detail, the ligand coordinated the catalytic Mg 2+ cofactor with its ketoacid moiety; the octahedral sphere was completed by Glu434, Asp462, and two water molecules, which were stabilized by further contacts with the acidic residues of the active site.…”

Section: β-Ketoacyl-acpm Synthase (Kasa)mentioning

confidence: 99%

“…It bound to the phospholipid (PL) binding site, forming hydrophobic interactions throughout the acyl channel, and establishing H bonds with Glu199 through its sulfonamide moiety [53]. In 2020, the same group designed a series of transposed indole derivatives to overcome the issues of 104 [51]. In 2018, Kumar and collaborators reported an indazole sulfonamide inhibitor, DG167 (104, Figure 49), which displayed an excellent MIC of 0.39 μM against Mtb H37Rv and a lack of cross-resistance with first-line drugs [53].…”

Section: β-Ketoacyl-acpm Synthase (Kasa)mentioning

confidence: 99%

“…It bound to the phospholipid (PL) binding site, forming hydrophobic interactions throughout the acyl channel, and establishing H bonds with Glu199 through its sulfonamide moiety [53]. In 2020, the same group designed a series of transposed indole derivatives to overcome the issues of 104 [51]. Crystallographic investigations around two members of this series (105 and 106, PDB: 6P9K and 6P9M, respectively; Figure 49) revealed that the two compounds bound to the same PL site.…”

Section: β-Ketoacyl-acpm Synthase (Kasa)mentioning

confidence: 99%

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An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

et al. 2021

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The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.

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A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Cited by 24 publications

References 65 publications

Morphological profiling of tubercle bacilli identifies drug pathways of action

Morphological profiling of tubercle bacilli identifies drug pathways of action

Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

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