Even in times of coronavirus, tuberculosis remains the deadliest infectious disease worldwide. It is estimated that a third of the population is affected by Mycobacterium tuberculosis, the bacterium responsible for tuberculosis. Each year, an average of 1.8 million people worldwide die from this disease. The secret to the success of the bacteria that cause tuberculosis lies in their ability to outwit the immune system. Their strategy is to hide inside macrophages, the immune system cells that specialize in fighting pathogens. Thus, these defense cells go from being protective agents to bacteria havens in ways that favor infection rather than fight it. It is what is known as the “macrophage paradox”, a paradox that occurs when infections originate from so-called intracellular bacteria.
Now, a study led by Professors Giuseppe Battaglia and Loris Rizzello from the Institute for Bioengineering of Catalonia (IBEC) together with research from several international institutions has shown the ability of synthetic vesicles to penetrate macrophages and specifically release drugs to lower and, in some cases, even eliminate infection. The paper, published in the ACS Nano journal, shows the efficacy of this therapy in reducing the bacterial load of macrophages infected by Mycobacterium tuberculosis as well as other intracellular bacteria. The researchers managed to totally eradicate infection according to the combination of drugs, in both in vitro experiments, with human cells, and in vivo, using the zebrafish as an animal model.
A faster, more effective and safer therapy
PMPC-PDPA polymersomes, developed by the Molecular Bionics Group, are synthetic nanoscopic vesicles that have drugs encapsulated within them. Thanks to the PMPC chemistry, when into contact with macrophages, these vesicles are phagocytosed and, once in the intracellular space, they release the corresponding drugs. The study demonstrates, on the one hand, the effectiveness of these vesicles in occupying the interior of macrophages—a process which occurs in a matter of minutes—and, on the other hand, the specificity when releasing the pharmacological load. Polymerosomes are highly stable under physiological pH conditions (pH 7.4) so when they are circulating in the body, they are not capable of releasing the drug they contain. In contrast, the drop in pH of the intracellular medium promotes pharmacological activation, thus preventing an unwanted distribution of the antibiotic in other places in the human body.
Lastly, the study also corroborates the safety of this therapeutic approach in regard to the possible changes that this mechanism could generate in the cellular metabolism of macrophages. In fact, the experts observed no difference between macrophages treated with polymersomes and untreated macrophages, nor was an inflammatory response detected due to the high concentration of polymersomes, thus confirming the harmlessness of the therapy.
Dismantling the antibiotic resistance of intracellular bacteria
Currently, the most widely used therapy to fight diseases such as tuberculosis consists of the combined administration of large amounts of antibiotics over a long period of time, ranging from 6 to 9 months. Thus, the existing treatments promote the emergence of multi-resistant bacteria capable of surviving under the action of antibiotics. Therefore, in the long term, they hinder the eradication of infections by intracellular bacteria.
This reality highlights the need to find alternative solutions that are more effective as well as fast, such as the one described in this article. In fact, the team of experts found in their study that synthetic vesicle therapy requires much lower doses than usual to obtain the same results as in traditional treatments. A very promising finding to beat infections as deadly as tuberculosis while addressing one of the biggest threats to global health: antibiotic resistance of intracellular bacteria.
Reference article: F. Fenaroli, J. D. Robertson, E. Scarpa, V. M. Gouveia, C. Di Guglielmo, C. De Pace, Ph. M. Elks, A. Poma, D. Evangelopoulos, J. Ortiz Canseco, H. M. Marriott, D. H. Dockrell, S. J. Foster, T. McHugh, S. A. Renshaw, J. Samitier Martí, G. Battaglia and L. Rizzello. Polymersomes eradicating intracellular bacteria, ACS Nano, 2020.
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