Antimycobacterial activity of UDP-galactopyranose mutase inhibitors

Borrelli, Silvia; Zandberg, Wesley F.; Mohan, Sankar; Ko, Mary; Martínez-Gutiérrez, Fidel; Partha, Sarathy Karunan; Sanders, D.A.R.; Av‐Gay, Yossef; Pinto, B. Mario

doi:10.1016/j.ijantimicag.2010.06.030

Cited by 32 publications

(39 citation statements)

References 14 publications

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“…Moreover, the presence of UGM homologues in a variety of pathogens suggests that UGM inhibitors could be useful against multiple classes of microbes. 10,16–23 We set out to devise cell-permeable UGM inhibitors that could be used as therapeutic leads and probes of the roles of Gal f -containing glycans.…”

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confidence: 99%

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Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

et al. 2015

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Galactofuranose (Galf) is present in glycans critical for the virulence and viability of several pathogenic microbes, including Mycobacterium tuberculosis, yet the monosaccharide is absent from mammalian glycans. Uridine 5′-diphosphate-galactopyranose mutase (UGM) catalyzes the formation of UDP-Galf, which is required to produce Galf-containing glycoconjugates. Inhibitors of UGM have therefore been sought, both as antimicrobial leads and as tools to delineate the roles of Galf in cells. Obtaining cell permeable UGM probes by either design or high throughput screens has been difficult, as has elucidating how UGM binds small molecule, noncarbohydrate inhibitors. To address these issues, we employed structure-based virtual screening to uncover new inhibitor chemotypes, including a triazolothiadiazine series. These compounds are among the most potent antimycobacterial UGM inhibitors described. They also facilitated determination of a UGM–small molecule inhibitor structure, which can guide optimization. A comparison of results from the computational screen and a high-throughput fluorescence polarization (FP) screen indicated that the scaffold hits from the former had been evaluated in the FP screen but missed. By focusing on promising compounds, the virtual screen rescued false negatives, providing a blueprint for generating new UGM probes and therapeutic leads.

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confidence: 99%

“…16,18–20,22,24–30 Though inhibitors have emerged, 18–20,31 few have been shown to function against microbial pathogens. We previously developed a fluorescence polarization (FP) assay to identify competitive UGM inhibitors.…”

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Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

et al. 2015

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“…A number of other molecules have been reported to target nonreplicating mycobacteria by disrupting steps of peptidoglycan biosynthesis, including: L,D-transpeptidases by faropenem ( compound 33 ) (38, 201); UDP-galactopyranose mutase ( compound 34 ) (202); phospho-N-acetylmuramoyl-pentapeptidetransferase (MurX) by CPZEN-45 ( compound 35 ) (203); and the capuramycin analogue UT-01320 ( compound 36 ) (204). CPZEN-45 may additionally target decaprenyl-phosphate-GlcNAc-1-transferase (WecA, encoded by rv1302 ), which has a role in synthesizing teichoic acid in Bacillus subtilis and mycoylarabinogalactan in mycobacteria (205).…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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“…These compounds, however, exhibited some toxicity to mammalian cells and were difficult to optimize. 15, 27 Through virtual screening, we found a family of triazolothiadiazine inhibitors (Figure 1) that possess improved physical properties and that are active against Mycobacterium tuberculosis . 15 We sought to optimize these inhibitors further by understanding the molecular basis of their affinity for UGM.…”

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confidence: 99%

Conformational Control of UDP-Galactopyranose Mutase Inhibition

et al. 2017

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UDP-galactopyranose mutase (Glf or UGM) catalyzes the formation of uridine 5′-diphosphate-α-D-galactofuranose (UDP-Galf) from UDP-galactopyranose (UDP-Galp). The enzyme is required for the production of Galf-containing glycans. UGM is absent in mammals, but members of the Corynebacterineae suborder require UGM for cell envelope biosynthesis. The need for UGM in some pathogens has prompted the search for inhibitors that could serve as antibiotic leads. Optimizing inhibitor potency, however, has been challenging. The UGM from Klebsiella pneumoniae (KpUGM), which is not required for viability, is more effectively impeded by small-molecule inhibitors than are essential UGMs from species such as Mycobacterium tuberculosis or Corynebacterium diphtheriae. Why KpUGM is more susceptible to inhibition than other orthologs is not clear. One potential source of difference is UGM ortholog conformation. We previously determined a structure of CdUGM bound to a triazolothiadiazine inhibitor in the open form, but it was unclear whether the small molecule inhibitor bound this form or to the closed form. By varying the terminal tag (CdUGM-His6 and GSG-CdUGM), we crystallized CdUGM to capture the enzyme in different conformations. These structures reveal a pocket in the active site that can be exploited to augment inhibitor affinity. Moreover, they suggest the inhibitor binds the open form of most prokaryotic UGMs but can bind the closed form of KpUGM. This model and the structures suggest strategies to optimize inhibitor potency by exploiting UGM conformational flexibility.

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Antimycobacterial activity of UDP-galactopyranose mutase inhibitors

Cited by 32 publications

References 14 publications

Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

Targeting Phenotypically TolerantMycobacterium tuberculosis

Conformational Control of UDP-Galactopyranose Mutase Inhibition

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