Role of Chemical Biology in Tuberculosis Drug Discovery and Diagnosis

Kolbe, Katharina; Veleti, Sri Kumar; Johnson, Emma E.; Cho, Young-Woo; Oh, Seung-Ha; Barry, Clifton E.

doi:10.1021/acsinfecdis.7b00242

Cited by 14 publications

(12 citation statements)

References 71 publications

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“…These applications, however, require molecular differentiation between highly similar enzyme substrates and identification of unique enzyme signatures that demarcate disease conditions (27,71,72). Esterases are a large class of enzymes with potential diagnostic applications in labeling infectious bacteria and therapeutic applications combating cancer, inflammation, and pathogenic infections (3,45,73). The substrate promiscuity of esterases has, however, hindered the construction of selective esterase probes for these applications (24,74).…”

Section: Discussionmentioning

confidence: 99%

Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases

White

Koelper

Russell

et al. 2018

Journal of Biological Chemistry

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Cellular esterases catalyze many essential biological functions by performing hydrolysis reactions on diverse substrates. The promiscuity of esterases complicates assignment of their substrate preferences and biological functions. To identify universal factors controlling esterase substrate recognition, we designed a 32-member structure-activity relationship (SAR) library of fluorogenic ester substrates and used this library to systematically interrogate esterase preference for chain length, branching patterns, and polarity to differentiate common classes of esterase substrates. Two structurally homologous bacterial esterases were screened against this library, refining their previously broad overlapping substrate specificity. esterase ybfF displayed a preference for γ-position thioethers and ethers, whereas Rv0045c from displayed a preference for branched substrates with and without thioethers. We determined that this substrate differentiation was partially controlled by individual substrate selectivity residues Tyr-119 in ybfF and His-187 in Rv0045c; reciprocal substitution of these residues shifted each esterase's substrate preference. This work demonstrates that the selectivity of esterases is tuned based on transition state stabilization, identifies thioethers as an underutilized functional group for esterase substrates, and provides a rapid method for differentiating structural isozymes. This SAR library could have multifaceted future applications, including imaging, biocatalyst screening, molecular fingerprinting, and inhibitor design.

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Section: Discussionmentioning

confidence: 99%

Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases

White

Koelper

Russell

et al. 2018

Journal of Biological Chemistry

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“…The therapeutic applications of esterases have continued to expand, especially as higher throughput analysis of virulence factors and esterases is probed more widely (Bachovchin & Cravatt, ; Kolbe et al, ). Recently, the esterases from Staphylococcus aureus were analyzed by ABPP, identifying 10 previously uncharacterized and evolutionarily divergent serine hydrolases nicknamed FphA–J (fluorophosphonate‐binding hydrolases) (Lentz et al, ).…”

Section: Bacterial Esterasesmentioning

confidence: 99%

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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“…The second category of probes are inspired by mycobacterial proteins and enzymes and are utilized for specific enzyme labeling as well as for the identification of novel therapeutic targets. Similar seminal reviews exist that deliberate exhaustively on activity-based protein profiling, 24,25 trehalose-based probes for bacterial imaging in vitro and in vivo, 26 and investigating mycobacterial cell envelope structure and functions. 24 However, this work, while discussing recent progress along similar lines, diverges by reviewing fairly recent progress in the field of infection biology focused on how some of these chemical probes based on Mtb lipids 27 can be employed for inventorying membrane-centric host−pathogen cross-talk.…”

Section: ■ Introductionmentioning

confidence: 97%

Chemical Tools for Illumination of Tuberculosis Biology, Virulence Mechanisms, and Diagnosis

2020

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Tuberculosis (TB) remains one of the deadliest infectious diseases and begs the scientific community to up the ante for research and exploration of completely novel therapeutic avenues. Chemical biology-inspired design of tunable chemical tools has aided in clinical diagnosis, facilitated discovery of therapeutics, and begun to enable investigation of virulence mechanisms at the host−pathogen interface of Mycobacterium tuberculosis. This Perspective highlights chemical tools specific to mycobacterial proteins and the cell lipid envelope that have furnished rapid and selective diagnostic strategies and provided unprecedented insights into the function of the mycobacterial proteome and lipidome. We discuss chemical tools that have enabled elucidating otherwise intractable biological processes by leveraging the unique lipid and metabolite repertoire of mycobacterial species. Some of these probes represent exciting starting points with the potential to illuminate poorly understood aspects of mycobacterial pathogenesis, particularly the host membrane−pathogen interactions.

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Role of Chemical Biology in Tuberculosis Drug Discovery and Diagnosis

Cited by 14 publications

References 71 publications

Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases

Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases

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

Chemical Tools for Illumination of Tuberculosis Biology, Virulence Mechanisms, and Diagnosis

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