An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis

Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup; Park, Annie S.; Zeiler, Evelyn; Raju, Ravikiran M.; Akopian, Tatos; Kandror, Olga; Sacchettini, James C.; Moody, D. Branch; Rubín, Eric J.; Sieber, Stephan A.

doi:10.1002/anie.201709365

Cited by 60 publications

(72 citation statements)

References 37 publications

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“…On the other hand, despite their high activity, phosphate inhibitors can be subjected to hydrolysis, rendering their covalent binding potentially reversible as shown here in the case of the CyC17-Ser124 adduct (29). Interestingly, using a chemical proteomic approach, the EZ120 -lactone compound exhibiting strong antitubercular activity and resembling an electrophilic mimic of mycolic acids was recently found to block several serine hydrolases essential for the mycomembrane biosynthesis (44). The polyketide synthase Pks13, whose -keto mycolate is transferred onto trehalose and reduced to yield TMM, as well as Ag85A were identified as primary targets of EZ120.…”

Section: Discussionmentioning

confidence: 96%

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo

Viljoen

Richard

Nguyen

et al. 2018

Journal of Biological Chemistry

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An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of Cyclipostins and Cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex (i.e. Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate (TDM) and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC7β, CyC8β, and CyC17 bind covalently to the catalytic Ser124 residue in Ag85C, inhibit mycolyltransferase activity, i.e. the transfer of a fatty acid molecule onto trehalose, and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC8β disclosed that this inhibitor occupies Ag85C's substrate-binding pocket. Importantly, metabolic labeling of M. tuberculosis cultures revealed that the CyC compounds impair both TDM synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex in vitro and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against M. tuberculosis. http://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 96%

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo

Viljoen

Richard

Nguyen

et al. 2018

Journal of Biological Chemistry

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“…With diverse targeting ligands including THL (Figure a,b) and fluorophosphonate (Figure c,d) derivatives, each of these proteomic ABPP studies has found overlapping but distinct subpopulations of esterase activity. Importantly, they have each identified esterases that remain active under dormant growth conditions (Lehmann et al, ; Ortega et al, ; Ravindran et al, ; Tallman et al, ). The distinct subclasses of esterases mapped from each study may relate to small variations in ABPP ligand properties, but interestingly none of these four studies have isolated LipY despite THL and fluorophosphonates being known inhibitors (Tallman et al, ).…”

Section: Bacterial Esterasesmentioning

confidence: 99%

“…To track the full repertoire of Mtb esterases, multiple recent studies have identified the proteome-wide esterase activity of Mtb and followed the change in Mtb esterase activity in relation to disease conditions (Lehmann et al, 2018;Ortega et al, 2016;Ravindran et al, 2014;Tallman et al, 2016b). By using activity-based protein profiling (ABPP) and various mechanism-based inhibitors (Figure 2a,d), more than 80 different serine hydrolases have been tagged across four recent Mtb ABPP studies (Tallman et al, 2016b).…”

Section: Mtb Esterasesmentioning

confidence: 99%

“…Importantly for prodrug ester design, dormant mycobacterial esterase activity showed a skewed substrate distribution, with its esterases preferring longer, FIGURE 2 Profiling bacterial esterases. (a-d) Activity-based protein profiling ligands used to characterize proteome-wide esterase activity in Mycobacteria and to identify esterase activity present under disease relevant growth conditions (Lehmann et al, 2018;Ortega et al, 2016;Ravindran et al, 2014;Tallman et al, 2016b). Each ligand contains an electrophilic moiety (labeled in red) for covalent labeling of esterases and an alkyne for isolation and identification of labeled esterases by click chemistry.…”

Section: Mtb Esterasesmentioning

confidence: 99%

“…(a) Tetrahydrolipstatin (THL)-alkyne (Ravindran et al, 2014). (b) Modified version of THL-alkyne (EZ120) designed to mimic mycolic acids on the Mtb mycomembrane (Lehmann et al, 2018). (c) Fluorophosphonate-PEG-alkyne (Ortega et al, 2016).…”

Section: Mtb Esterasesmentioning

confidence: 99%

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Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance

Larsen

Johnson

2018

Drug Development Research

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The rise of antibiotic resistance necessitates the search for new platforms for drug development. Prodrugs are common tools for overcoming drawbacks typically associated with drug formulation and delivery, with ester prodrugs providing a classic strategy for masking polar alcohol and carboxylic acid functionalities and improving cell permeability. Ester prodrugs are normally designed to have simple ester groups, as they are expected to be cleaved and reactivated by a wide spectrum of cellular esterases. However, a number of pathogenic and commensal microbial esterases have been found to possess significant substrate specificity and can play an unexpected role in drug metabolism. Ester protection can also introduce antimicrobial properties into previously nontoxic drugs through alterations in cell permeability or solubility. Finally, mutation to microbial esterases is a novel mechanism for the development of antibiotic resistance. In this review, we highlight the important pathogenic and xenobiotic functions of microbial esterases and discuss the development and application of ester prodrugs for targeting microbial infections and combating antibiotic resistance. Esterases are often overlooked as therapeutic targets. Yet, with the growing need to develop new antibiotics, a thorough understanding of the specificity and function of microbial esterases and their combined action with ester prodrug antibiotics will support the design of future therapeutics.

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Peptide Mediated Chiral Inorganic Nanomaterials for Combating Gram‐Negative Bacteria

Wang

Hao

Sun

et al. 2018

Adv Funct Materials

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Antibiotic resistance is a severe problem worldwide. To address this issue, nanomaterials are applied to combat bacteria. On account of their high biocompatibility, easy surface modifications, and admirable optical properties, quantum dots are widely researched. Here, l-type cysteine (l-Cys)-decorated cadmium telluride (CdTe) nanoparticles (NPs) as an agent to combat bacteria based on their photoinduced oxidation feature are reported. Interestingly, l-Cys CdTe mixed with salmon sperm DNA and then illuminated by right circularly polarized light (RCP) will lead to reaction oxygen species (ROS) production. To achieve a high local concentration of ROS around the membrane and selective adherence to gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa in this study), l-Cys CdTe is decorated with a polycationic nonapeptide (PCNP-l-Cys CdTe). Upon irradiation, the bacterial membrane is severely damaged by the resulting high local ROS concentration. In addition, PCNP-l-Cys CdTe, which has intrinsic fluorescence characteristics, shows outstanding fluorescence imaging ability in vivo. It is successfully applied to the fluorescence imaging-guided bacterial infection therapy.

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An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis

Cited by 60 publications

References 37 publications

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo

Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance

Peptide Mediated Chiral Inorganic Nanomaterials for Combating Gram‐Negative Bacteria

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