Kinetically Controlled Drug Resistance

Sun, Xin; Hansen, Bertel; Hedstrom, Lizbeth

doi:10.1074/jbc.m111.305235

Cited by 7 publications

(5 citation statements)

References 21 publications

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“…This suggests that in Cryptococcus IMPDH, MPA binds to additional enzyme forms such as free enzyme or E -IMP. Such a scenario is also found in MPA-resistant Penicillium brevicompactum IMPDH, where the initial hydride transfer step (as opposed to the subsequent hydrolysis step) is either partially or completely rate-limiting, resulting in the predominate enzyme form being E -IMP-NAD + instead of E -XMP*, conferring MPA resistance [46] .…”

Section: Resultsmentioning

confidence: 91%

“…Recent work also demonstrates that if the initial hydride transfer step becomes rate-limiting, this reduces accumulation of the enzyme-substrate covalent complex and thus reduces susceptibility to MPA inhibition. Notably, this has occurred in MPA-resistant Penicillium brevicompactum IMPDH without significant residue changes around the substrate/cofactor binding sites [46] , [58] . Our work demonstrates that MPA binds to additional cryptococcal IMPDH forms (an uncompetitive inhibitor should bind only to the enzyme-substrate covalent complex), suggesting the enzyme to be fundamentally functionally different from the human isoforms.…”

Section: Discussionmentioning

confidence: 99%

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De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

et al. 2012

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We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival in vivo. Loss of inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway results in slow growth and virulence factor defects, while loss of the cognate phosphoribosyltransferase in the salvage pathway yielded no phenotypes. Further, the Cryptococcus species complex displays variable sensitivity to the IMPDH inhibitor mycophenolic acid, and we uncover a rare drug-resistant subtype of C. gattii that suggests an adaptive response to microbial IMPDH inhibitors in its environmental niche. We report the structural and functional characterization of IMPDH from Cryptococcus, revealing insights into the basis for drug resistance and suggesting strategies for the development of fungal-specific inhibitors. The crystal structure reveals the position of the IMPDH moveable flap and catalytic arginine in the open conformation for the first time, plus unique, exploitable differences in the highly conserved active site. Treatment with mycophenolic acid led to significantly increased survival times in a nematode model, validating de novo GTP biosynthesis as an antifungal target in Cryptococcus.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

et al. 2012

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“…A previous study found that a single residue showed mycophenolic acid resistance, although the binding sites were identical [65]. The kinetic mechanism was controlled for the mycophenolic acid resistance of PbIMPDH-A and PbIMPDH-B [66]. These studies showed that virtual screening by simple prediction is fast and low cost, although experimental verification is needed.…”

Section: Inhibitory Assay Against Clas Impdh∆98-201 Activitymentioning

confidence: 88%

Evaluation of Bronopol and Disulfiram as Potential Candidatus Liberibacter asiaticus Inosine 5′-Monophosphate Dehydrogenase Inhibitors by Using Molecular Docking and Enzyme Kinetic

et al. 2020

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Citrus huanglongbing (HLB) is a destructive disease that causes significant damage to many citrus producing areas worldwide. To date, no strategy against this disease has been established. Inosine 5′-monophosphate dehydrogenase (IMPDH) plays crucial roles in the de novo synthesis of guanine nucleotides. This enzyme is used as a potential target to treat bacterial infection. In this study, the crystal structure of a deletion mutant of CLas IMPDHΔ98-201 in the apo form was determined. Eight known bioactive compounds were used as ligands for molecular docking. The results showed that bronopol and disulfiram bound to CLas IMPDHΔ98-201 with high affinity. These compounds were tested for their inhibition against CLas IMPDHΔ98-201 activity. Bronopol and disulfiram showed high inhibition at nanomolar concentrations, and bronopol was found to be the most potent molecule (Ki = 234 nM). The Ki value of disulfiram was 616 nM. These results suggest that bronopol and disulfiram can be considered potential candidate agents for the development of CLas inhibitors.

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“…The biosynthetic cluster of MPA revealed an additional copy of IMPDH (Fig. 1A), which is insensitive to MPA, thus conferring resistance (13–15). Another example is fellutamide B, a proteasome inhibitor produced by Aspergillus nidulans.…”

Section: Introductionmentioning

confidence: 99%

Resistance Gene-Directed Genome Mining of 50 Aspergillus Species

2019

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Species belonging to the Aspergillus genus are known to produce a large number of secondary metabolites; some of these compounds are used as pharmaceuticals, such as penicillin, cyclosporine, and statin. With whole-genome sequencing, it became apparent that the genetic potential for secondary metabolite production is much larger than expected. As an increasing number of species are whole-genome sequenced, thousands of secondary metabolite genes are predicted, and the question of how to selectively identify novel bioactive compounds from this information arises. To address this question, we have created a pipeline to predict genes involved in the production of bioactive compounds based on a resistance gene hypothesis approach.

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Kinetically Controlled Drug Resistance

Abstract: Background: Mycophenolic acid sensitivity varies by 10

Cited by 7 publications

References 21 publications

De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

Evaluation of Bronopol and Disulfiram as Potential Candidatus Liberibacter asiaticus Inosine 5′-Monophosphate Dehydrogenase Inhibitors by Using Molecular Docking and Enzyme Kinetic

Resistance Gene-Directed Genome Mining of 50 Aspergillus Species

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