Exploiting one infection to control another: phages versus mycobacteria

Edna George

A team of researchers from the Indian Institute of Science, Bengaluru has explored a new approach to treat mycobacterial infections, which are becoming increasingly drug-resistant. They found that a cocktail of mycobacteriophages – viruses that infect mycobacteria but not humans– were effective against slow- and fast-growing mycobacteria, in cultures. This has clinical significance in treating tuberculosis (caused by M. tuberculosis, a slow-growing mycobacterium), which is of concern, especially in developing countries. In this article, Edna George reports on this recent study by Rachit Agarwal’s team.

Edna phage
An electron micrograph of bacteriophages attached to a bacterial cell. By Dr Graham Beards - en:Image:Phage.jpg, CC BY-SA 3.0,

Mycobacterial infections have been a lingering concern due to their high incidence and growing antibiotic resistance. A team of researchers led by Rachit Agarwal, Assistant Professor at the Centre for BioSystems Science and Engineering, Indian Institute of Science (IISc), Bengaluru tried a different approach to control mycobacterial infections, by exploring the potential of phages for infection management.

Among the various mycobacterial infections, tuberculosis (TB) is one of the leading causes of death worldwide and poses a global health hazard. According to the World Health Organization (WHO) annual TB report published in 2021, nearly 9.9 million people are ill due to TB and 1.3 million deaths have been estimated. This necessitates novel treatment or vaccines in addition to improved diagnostics and better health coverage.

Tuberculosis — a communicable disease, often transmitted through the air — is characterized by infection of specialized immune cells in the lungs. Although these immune cells fire an immune response, the bacteria outsmart them by surviving in adverse conditions. Tuberculosis has been of special concern due to its high occurrence in developing countries, the requirement for long-term treatment and the development of multi-drug resistance. Hence, irrespective of current treatment strategies, much research has been dedicated to device better therapy measures to control and fight the disease. 

An earlier study has shown the potential of using phages, which are specific to bacteria but harmless to humans, to treat bacterial infections in a cystic fibrosis patient. Inspired by this study, Rachit Agarwal’s team utilized viruses that infect, multiply, and kill bacterial cells — known as bacteriophages or simply phages — to design an anti-mycobacterial therapy. To test the possibility of using phage therapy for controlling mycobacterial infections, we first started experiments with Mycobacterium smegmatis (a faster growing species of mycobacteria) and were excited with the initial success. That led us to perform a detailed study to understand if phages are effective in various pathophysiological conditions,” says Agarwal. The initial observation of reduced mycobacterial growth within 2 – 5 hours of introducing phages seemed encouraging. Therefore, similar studies were carried out using phage cocktails, which also resulted in the decrease of bacterial growth. Agarwal’s team decided to further explore the possibilities of using these phage cocktails to effectively treat mycobacterial infections. 

M. smegmatis is a fast-growing mycobacterial species when compared to other mycobacterial species. During infection, mycobacteria usually thrive in adverse conditions often characterized by low levels of pH, nutrition and oxygen. Therefore, further experiments were conducted under such adverse conditions using M. smegmatis to observe quantifiable results. Subsequently, detailed studies under disease-mimicking adverse conditions showed that phages were effective in decreasing mycobacterial growth.

M. tuberculosis (Mtb), the causative agent of tuberculosis, is an example of a slow-growing mycobacterium. Owing to the impact of tuberculosis on global health, phage therapy was used in combination with the antibiotics that are currently used to treat tuberculosis. M. smegmatis cultures were co-treated with phages and antibiotics, and a significant reduction in mycobacterial growth was observed. Given these optimistic results in M. smegmatis, phage treatment was tried on an avirulent strain (a non-disease causing variety) of M. tuberculosis, and successful prevention of mycobacterial growth was observed up to 57 days.

This study, on understanding the infection dynamics of phages in slow- and fast-growing mycobacteria, is important due to its clinical significance in treating tuberculosis. Amit Singh, Associate Professor at the Department of Microbiology and Cell Biology, IISc, explains the importance of the study: The study showed that phages are synergetic with the clinically-relevant anti-TB drugs. Therefore, phages can be used against drug-resistant mycobacteria. However, the true potential of these approaches requires future efficacy studies using mycobacteriophages cocktails for targeting pathogenic Mtb inside the infected human host cells.”

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