2. Academic Validation
  3. An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus

An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus

  • Sci Transl Med. 2024 Feb 21;16(735):eadi7558. doi: 10.1126/scitranslmed.adi7558.
Kaixi Zhang 1,  Jakkarin Limwongyut 1 2,  Alex S Moreland 2,  Samuel Chan Jun Wei 1,  Tania Jim Jia Min 1,  Yan Sun 3,  Sung Jae Shin 4,  Su-Young Kim 5,  Byung Woo Jhun 5,  Kevin Pethe 3 6 7,  Guillermo C Bazan 1 2 6 8
Affiliations

Affiliations

  • 1 Department of Chemistry, National University of Singapore, 4 Science Drive 2, 117543 Singapore, Singapore.
  • 2 Center for Polymers and Organic Solids, Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
  • 3 Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, 636921 Singapore, Singapore.
  • 4 Department of Microbiology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • 5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
  • 6 Singapore Centre on Environmental Life Sciences Engineering (SCELSE), 60 Nanyang Drive, 639798 Singapore, Singapore.
  • 7 National Centre for Infectious Diseases (NCID), 16 Jalan Tan Tock Seng, 308442 Singapore, Singapore.
  • 8 Institute for Functional Intelligent Materials (I-FIM), National University of Singapore, 117544 Singapore, Singapore.
PMID: 38381846 DOI: 10.1126/scitranslmed.adi7558
Abstract

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.

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