Health, Singapore (Commonwealth Union) – The specter of antibiotic resistance looms large over today’s healthcare landscape, diminishing our ability to effectively combat once manageable infections. Among these, nontuberculous mycobacteria infections stand out for their tenacious resistance to traditional treatments and their tendency to target individuals with underlying lung conditions like bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. The elderly and those with pre-existing health issues are especially susceptible, with infection rates doubling in these demographics and contributing significantly to rising public health expenditures.
Addressing this pressing issue, researchers from the Institute for Functional Intelligent Materials (I-FIM) at the National University of Singapore (NUS) have developed a promising solution. Their innovation, a compound based on conjugated oligoelectrolyte (COE) called COE-PNH2, holds the potential to revolutionize the treatment of persistent lung infections. Notably, COE-PNH2 exhibits potent efficacy against Mycobacterium abscessus (Mab), a prevalent species of mycobacteria, while also demonstrating a favorable safety profile.
The interdisciplinary study, partly supported by the NUS Yong Loo Lin School of Medicine’s Kickstart Initiative, was recently published in the prestigious scientific journal Science Translational Medicine on February 21, 2024. The Kickstart Initiative, a translational medicine program focused on advancing promising biomedical research projects from NUS Medicine to the market, provided critical funding for this research.
Led by Professor Guillermo Bazan, a principal investigator at I-FIM and the Department of Pharmacology at NUS Medicine, the study was conducted in collaboration with Associate Professor Kevin Pethe, who holds the Provost’s Chair in Infectious Disease at Nanyang Technological University, Singapore’s Lee Kong Chian School of Medicine (LKCMedicine).
Researchers of the study highlighted the fact that individuals suffering from nontuberculous mycobacteria infections often encounter numerous obstacles in their treatment journey. The prescribed regimens are demanding, with cure rates proving unsatisfactory, and the burden of side effects can be overwhelming. Even when it seems the infection has been effectively controlled, the specter of relapse looms ominously.
The researchers further indicated that traditional antibiotics frequently prove ineffective against these resilient pathogens. The unusually thick and impermeable cell envelope, coupled with the bacteria’s adept evolutionary adaptations, render them highly resistant to conventional treatments. Moreover, the bacteria’s ability to enter a dormant state, known as persisters, presents a formidable challenge in antibiotic therapy. These persisters often survive standard treatments, paving the way for relapse.
Enter COEs, a novel class of antimicrobial compounds characterized by their adaptable molecular structure. COEs can be tailored into a myriad of therapeutic agents capable of combating a wide range of infections. According to Professor Bazan, a lead author of the study, COEs represent a paradigm shift in antibiotic design. Their distinctive structure enables them to interact spontaneously with lipid bilayers, breaching the bacterial defenses that frequently thwart existing drugs.
One such molecule, COE-PNH2, meticulously engineered by researchers at I-FIM, is optimized to target nontuberculous mycobacteria. Employing a dual mechanism, it disrupts the bacterial membrane and obstructs vital bioenergetic pathways—a formidable combination that leaves the bacteria with little refuge. Importantly, COE-PNH2 attacks both replicating and dormant forms of the bacteria, demonstrating robust bactericidal activity. This comprehensive eradication approach minimizes the likelihood of resistance emergence and reduces the risk of relapse.
“Resistance development is often the Achilles’ heel of new antibiotics,” explained Professor Bazan. “COE-PNH2 exhibited a low frequency of resistance in our study, which suggests that it may remain effective longer than existing treatments, providing patients with a more durable solution.”
The new antibiotic prioritizes safety as a fundamental aspect. It has shown minimal toxicity in mammalian cells and did not trigger red blood cell destruction (haemolysis) even at concentrations significantly higher than those necessary for its antibacterial action. This noncytotoxic characteristic highlights the considerable safety margin of COE-PNH2 as a potential therapeutic agent.
Moreover, this safety profile is corroborated by in vivo studies. In a preclinical model of acute lung infection, the novel compound demonstrated excellent tolerance while exhibiting significant therapeutic efficacy. It notably reduced bacterial load without fostering the development of resistant strains.
“As COE is a relatively new antibiotic platform, the subsequent phase of this study requires us to understand the mechanism of action of the drug in greater detail,” said the corresponding author of the study Associate Professor Pethe, who made a note that moving the novel compound along from the petri dish and in vivo studies to patient is a task underway.
