Repurposing drugs to treat antimicrobial resistant infectious diseases

Interactions between carbohydrates (glycans) on the surface of infectious disease pathogens or host cells are often essential drivers of disease processes. Our core strategy for countering infectious diseases is to first identify essential glyco-interactions using systems biology approaches (glycomics) and then to screen for inhibitors of these interactions using a high-throughput surface plasmon resonance (SPR) screen, combined with in silco approaches, to generate candidate inhibitors. A recent exemplar study identified an essential interaction between a glycosylation on the pili of the bacterial pathogen Neisseria gonorrhoeae and complement receptor 3 on human cervical epithelial cells. A library of 3,141 drugs and nutraceuticals was screened for binding to the human I-domain by SPR. We identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection in ex vivo models of infection. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections. This study, and other recent examples of repurposing drugs to target drug resistant infectious disease will be presented.

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Publisher: REPO4EU

Publication date (Electronic, pub): 4 October 2023

Affiliations

[1 ] Institute for Glycomics, Griffith University, Gold Coast (Australia) ( https://ror.org/02sc3r913)

Author information

Michael Jennings https://orcid.org/0000-0002-1027-4684

Article

DOI: 10.58647/REXPO.23019

SO-VID: acff90c8-1b35-45c0-a3c8-2c1e8986911a

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Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

Conference name: RExPO23

Conference number: 2

Conference location: Stockholm, Sweden

Conference date: 25-26 October 2023

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REPO4EU

References

Poole Jessica, Day Christopher J., von Itzstein Mark, Paton James C., Jennings Michael P.. Glycointeractions in bacterial pathogenesis. Nature Reviews Microbiology. Vol. 16(7):440–452. 2018. Springer Science and Business Media LLC. [Cross Ref]
Shewell Lucy K., Day Christopher J., De Bisscop Xavier, Edwards Jennifer L., Jennings Michael P.. Repurposing Carbamazepine To Treat Gonococcal Infection in Women: Oral Delivery for Control of Epilepsy Generates Therapeutically Effective Levels in Vaginal Secretions. Antimicrobial Agents and Chemotherapy. Vol. 67(1)2023. American Society for Microbiology. [Cross Ref]
Poole Jessica, Day Christopher J., Haselhorst Thomas, Jen Freda E.-C., Torres Victor J., Edwards Jennifer L., Jennings Michael P.. Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells. mBio. Vol. 11(2)2020. American Society for Microbiology. [Cross Ref]

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[1] Poole Jessica, Day Christopher J., von Itzstein Mark, Paton James C., Jennings Michael P.. Glycointeractions in bacterial pathogenesis. Nature Reviews Microbiology. Vol. 16(7):440–452. 2018. Springer Science and Business Media LLC. [Cross Ref]

[2] Shewell Lucy K., Day Christopher J., De Bisscop Xavier, Edwards Jennifer L., Jennings Michael P.. Repurposing Carbamazepine To Treat Gonococcal Infection in Women: Oral Delivery for Control of Epilepsy Generates Therapeutically Effective Levels in Vaginal Secretions. Antimicrobial Agents and Chemotherapy. Vol. 67(1)2023. American Society for Microbiology. [Cross Ref]

[3] Poole Jessica, Day Christopher J., Haselhorst Thomas, Jen Freda E.-C., Torres Victor J., Edwards Jennifer L., Jennings Michael P.. Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells. mBio. Vol. 11(2)2020. American Society for Microbiology. [Cross Ref]