An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus

Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Curren...

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Main Authors: Zhang, Kaixi, Limwongyut, Jakkarin, Moreland, Alex S., Wei, Samuel Chan Jun, Jim, Tania Jia Min, Sun, Yan, Shin, Sung Jae, Kim, Su-Young, Jhun, Byung Woo, Pethe, Kevin, Bazan, Guillermo C.
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/174790
https://www.science.org/doi/10.1126/scitranslmed.adi7558
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spelling sg-ntu-dr.10356-1747902024-04-21T15:41:06Z An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus Zhang, Kaixi Limwongyut, Jakkarin Moreland, Alex S. Wei, Samuel Chan Jun Jim, Tania Jia Min Sun, Yan Shin, Sung Jae Kim, Su-Young Jhun, Byung Woo Pethe, Kevin Bazan, Guillermo C. Lee Kong Chian School of Medicine (LKCMedicine) National University of Singapore National Centre for Infectious Diseases (NCID) University of California Yonsei University College of Medicine Sungkyunkwan University School of Medicine Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) Medicine, Health and Life Sciences Mycobacterium abscessus Conjugated oligoelectrolyte Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects. We report here a potent anti-Mab compound from the flexible molecular framework afforded by conjugated oligoelectrolytes (COEs). A screen of structurally diverse, noncytotoxic COEs identified a lead compound, COE-PNH2, which was bactericidal against replicating, nonreplicating persisters and intracellular Mab.COE-PNH2 had low propensity for resistance development, with a frequency of resistance below 1.25 × 10-9 and showed no detectable resistance upon serial passaging. Mechanism of action studies were in line with COE-PNH2 affecting the physical and functional integrity of the bacterial envelope and disrupting the mycomembrane and associated essential bioenergetic pathways. Moreover, COE-PNH2 was well-tolerated and efficacious in a mouse model of Mab lung infection. This study highlights desirable in vitro and in vivo potency and safety index of this COE structure, which represents a promising anti-mycobacterial to tackle an unmet medical need. National University of Singapore (NUS), Temasek Laboratories Published version This study was funded by a National University of Singapore Start-up grant (to G.C.B.) and National University of Singapore Yong Loo Lin School of Medicine Kickstart Initiative grant NUHSRO/2022/014/Kickstart/12/LOA (to G.C.B.). 2024-04-16T05:21:31Z 2024-04-16T05:21:31Z 2024 Journal Article Zhang, K., Limwongyut, J., Moreland, A. S., Wei, S. C. J., Jim, T. J. M., Sun, Y., Shin, S. J., Kim, S., Jhun, B. W., Pethe, K. & Bazan, G. C. (2024). An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus. Science Translational Medicine, 16(735). https://dx.doi.org/10.1126/scitranslmed.adi7558 1946-6234 https://hdl.handle.net/10356/174790 10.1126/scitranslmed.adi7558 38381846 2-s2.0-85185826310 https://www.science.org/doi/10.1126/scitranslmed.adi7558 735 16 en NUHSRO/2022/014/Kickstart/12/LOA Science Translational Medicine © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. This article may be downloaded for personal use only. Any other use requires prior permission of the copyright holder. The Version of Record is available online at http://doi.org/10.1126/scitranslmed.adi7558. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
Mycobacterium abscessus
Conjugated oligoelectrolyte
spellingShingle Medicine, Health and Life Sciences
Mycobacterium abscessus
Conjugated oligoelectrolyte
Zhang, Kaixi
Limwongyut, Jakkarin
Moreland, Alex S.
Wei, Samuel Chan Jun
Jim, Tania Jia Min
Sun, Yan
Shin, Sung Jae
Kim, Su-Young
Jhun, Byung Woo
Pethe, Kevin
Bazan, Guillermo C.
An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
description Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects. We report here a potent anti-Mab compound from the flexible molecular framework afforded by conjugated oligoelectrolytes (COEs). A screen of structurally diverse, noncytotoxic COEs identified a lead compound, COE-PNH2, which was bactericidal against replicating, nonreplicating persisters and intracellular Mab.COE-PNH2 had low propensity for resistance development, with a frequency of resistance below 1.25 × 10-9 and showed no detectable resistance upon serial passaging. Mechanism of action studies were in line with COE-PNH2 affecting the physical and functional integrity of the bacterial envelope and disrupting the mycomembrane and associated essential bioenergetic pathways. Moreover, COE-PNH2 was well-tolerated and efficacious in a mouse model of Mab lung infection. This study highlights desirable in vitro and in vivo potency and safety index of this COE structure, which represents a promising anti-mycobacterial to tackle an unmet medical need.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Zhang, Kaixi
Limwongyut, Jakkarin
Moreland, Alex S.
Wei, Samuel Chan Jun
Jim, Tania Jia Min
Sun, Yan
Shin, Sung Jae
Kim, Su-Young
Jhun, Byung Woo
Pethe, Kevin
Bazan, Guillermo C.
format Article
author Zhang, Kaixi
Limwongyut, Jakkarin
Moreland, Alex S.
Wei, Samuel Chan Jun
Jim, Tania Jia Min
Sun, Yan
Shin, Sung Jae
Kim, Su-Young
Jhun, Byung Woo
Pethe, Kevin
Bazan, Guillermo C.
author_sort Zhang, Kaixi
title An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
title_short An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
title_full An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
title_fullStr An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
title_full_unstemmed An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus
title_sort anti-mycobacterial conjugated oligoelectrolyte effective against mycobacterium abscessus
publishDate 2024
url https://hdl.handle.net/10356/174790
https://www.science.org/doi/10.1126/scitranslmed.adi7558
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