Breakthrough antibiotic for mycobacterial infections

Singaporean researchers have assembled a new antibiotic candidate that appears to be effective against hard-to-treat mycobacterial lung diseases, according to a study published in the journal Science Translational Medicine.

Nontuberculous mycobacteria infections have a penchant for afflicting those with existing lung diseases, such as bronchiectasis, chronic obstructive pulmonary disease and cystic fibrosis. The bacteria’s uncharacteristically thick and impermeable cell envelope, as well as a shrewd evolutionary sleight of hand, has made the pathogen especially resistant towards common treatments. Additionally, the ability of the bacteria to enter a dormant state — forming what is referred to as persisters — poses a daunting challenge in antibiotic therapy, as these persisters often survive traditional treatments only to cause relapse.

Researchers from the Institute for Functional Intelligent Materials (I-FIM) at the National University of Singapore (NUS) have now created a conjugated oligoelectrolyte (COE)-based compound that has the potential to turn the tide on this disease. A class of antimicrobial compounds with a modular molecular framework, COEs can be engineered into a panoply of therapeutic agents to fight a broad spectrum of infections.

“COEs represent a fundamentally different approach to antibiotic design,” said Professor Guillermo Bazan, a principal investigator at I-FIM and corresponding author on the new study. “Their unique structure, which facilitates the spontaneous interaction with lipid bilayers, allows them to breach the bacterial defences that so often thwart existing drugs.”

The I-FIM-designed molecule, named COE-PNH2, has been optimised to target Mycobacterium abscessus (Mab) — one of the most prevalent mycobacteria species. It employs a dual mechanism that disrupts the bacterial membrane and obstructs vital bioenergetic pathways — a one-two punch that leaves the bacteria with little room to hide. In particular, the molecule attacks both replicating and dormant forms of Mab, exhibiting robust bactericidal activity that leads to a more comprehensive eradication of the bacteria, leaving no refuge for resistance to crop up while reducing the likelihood of relapse.

“Resistance development is often the Achilles’ heel of new antibiotics,” Bazan said. “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 antibiotic demonstrated low toxicity in mammalian cells and did not induce the destruction of red blood cells (haemolysis) at concentrations far exceeding those required for antibacterial activity. Its high level of safety has also been reinforced through in vivo studies — when tested in a preclinical model of acute lung infection, the novel compound was well-tolerated while its therapeutic effect was pronounced, achieving a substantial reduction in bacterial load without the emergence of resistant strains.

Associate Professor Kevin Pethe, co-corresponding author of the study, acknowledged that COE is a relatively new antibiotic platform and so the subsequent phase of the study requires the researchers to understand the mechanism of action of the drug in greater detail. For one thing, unravelling the molecular interaction between COE-PNH2 and mammalian and bacterial cell membranes is crucial. There is also a need to dissect various mechanisms through which the compound functions; for instance, it is unclear to the researchers whether the hydrogen-bonding moieties of the compound contribute to its enhanced potency against nutrient-starved persisters. Uncovering the precise manner in which COE-PNH2 compromises these resilient forms could shine new light on more effective strategies for combating dormant bacterial strains.

Intriguingly, the researchers have also discovered the presence of intracellular vesicles in Mab treated with COE-PNH2. Are these vesicles by-products of disrupted bioenergetics, or do they form as a result of physical interactions between the compound and the membrane lipids? The answers may provide vital insights into how COE-PNH2 exerts its antimicrobial action and inform the development of interventions for other hard-to-treat pathogens.

Image caption: COE-PNH2 eradicates bacteria thoroughly, eliminating any potential grounds for resistance while reducing the likelihood of relapse.