Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA

Kumar, Pradeep; Capodagli, Glenn C.; Awasthi, Divya; Shrestha, Riju; Maharaja, Karishma; Sukheja, Paridhi; Li, Shao Gang; Inoyama, Daigo; Zimmerman, Matthew; Liang, Hsin Pin Ho; Sarathy, Jansy; Mina, Marizel; Rasic, George; Russo, Riccardo; Perryman, Alexander L.; Richmann, Todd; Gupta, Aditi; Singleton, Eric; Verma, Sheetal; Husain, Shahid; Soteropoulos, Patricia; Wang, Zhe; Morris, Roxanne; Porter, Gene; Agnihotri, Gautam; Salgame, Padmini; Ekins, Sean; Rhee, Kyu Y.; Connell, Nancy; Dartois, Véronique; Neiditch, Matthew B.; Freundlich, Joel S.; Alland, David

doi:10.1128/mbio.02101-17

Cited by 40 publications

(77 citation statements)

References 55 publications

(89 reference statements)

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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: 78%

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: 78%

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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“…Highly similar scaffolds with completely different targets have been reported previously; for example, very closely related indazole sulfonamides have been reported to be potent inhibitors of inosine monophosphate dehydrogenase 25 and the β-ketoacyl-ACP synthase involved in mycolic acid biosynthesis. 26 Such profound changes in the target with closely related structures suggests that the chemical clustering of the hit series, as is commonly done in Mtb whole-cell-based screening programs, must be done with additional care when selecting a hit series and interpreting the SAR in the absence of mechanistic information.…”

Section: Discussionmentioning

confidence: 99%

Structure–Activity Relationships of Pyrazolo[1,5-a]pyrimidin-7(4H)-ones as Antitubercular Agents

Azeeza

Pauly

et al. 2021

ACS Infect. Dis.

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Pyrazolo[1,5- a ]pyrimidin-7(4 H )-one was identified through high-throughput whole-cell screening as a potential antituberculosis lead. The core of this scaffold has been identified several times previously and has been associated with various modes of action against Mycobacterium tuberculosis ( Mtb ). We explored this scaffold through the synthesis of a focused library of analogues and identified key features of the pharmacophore while achieving substantial improvements in antitubercular activity. Our best hits had low cytotoxicity and showed promising activity against Mtb within macrophages. The mechanism of action of these compounds was not related to cell-wall biosynthesis, isoprene biosynthesis, or iron uptake as has been found for other compounds sharing this core structure. Resistance to these compounds was conferred by mutation of a flavin adenine dinucleotide (FAD)-dependent hydroxylase (Rv1751) that promoted compound catabolism by hydroxylation from molecular oxygen. Our results highlight the risks of chemical clustering without establishing mechanistic similarity of chemically related growth inhibitors.

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“…The indazole sulfonamide series exemplified by 28 ( Table 2 ) was identified in screens of a GSK compound library ( Ballell et al., 2013 ; Kumar et al., 2018 ). This scaffold possessed the attributes of an attractive compound for drug discovery as evidenced by its Mtb potency, selectivity for Mtb , excellent physicochemical characteristics and promising in vitro DMPK profile ( Abrahams et al., 2016 ).…”

Section: Antitubercular Agents Inhibiting Mycolic Acid Biosynthesismentioning

confidence: 99%

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

Trifonov

Yadav

et al. 2021

Front. Cell. Infect. Microbiol.

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More than two decades have elapsed since the publication of the first genome sequence of Mycobacterium tuberculosis (Mtb) which, shortly thereafter, enabled methods to determine gene essentiality in the pathogen. Despite this, target-based approaches have not yielded drugs that have progressed to clinical testing. Whole-cell screening followed by elucidation of mechanism of action has to date been the most fruitful approach to progressing inhibitors into the tuberculosis drug discovery pipeline although target-based approaches are gaining momentum. This review discusses scaffolds that have been identified over the last decade from screens of small molecule libraries against Mtb or defined targets where mechanism of action investigation has defined target-hit couples and structure-activity relationship studies have described the pharmacophore.

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Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA

Cited by 40 publications

References 55 publications

Morphological profiling of tubercle bacilli identifies drug pathways of action

Morphological profiling of tubercle bacilli identifies drug pathways of action

Structure–Activity Relationships of Pyrazolo[1,5-a]pyrimidin-7(4H)-ones as Antitubercular Agents

Tuberculosis Drug Discovery: A Decade of Hit Assessment for Defined Targets

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