Mycobacteriophages to Treat Tuberculosis: Dream or Delusion?

Abstract

Rates of antimicrobial resistance are increasing globally while the pipeline of new antibiotics is drying up, putting patients with disease caused by drug-resistant bacteria at increased risk of complications and death. The growing costs for diagnosis and management of drug resistance threaten tuberculosis control where the disease is endemic and resources limited. Bacteriophages are viruses that attack bacteria. Phage preparations served as anti-infective agents long before antibiotics were discovered. Though small in size, phages are the most abundant and diverse biological entity on earth. Phages have co-evolved with their hosts and possess all the tools needed to infect and kill bacteria, independent of drug resistance. Modern biotechnology has improved our understanding of the biology of phages and their possible uses. Phage preparations are available to treat meat, fruit, vegetables, and dairy products against parasites or to prevent contamination with human pathogens, such as <i>Listeria monocytogenes, Escherichia coli</i>, or <i>Staphylococcus aureus</i>. Such phage-treated products are considered fit for human consumption. A number of recent case reports describe in great detail the successful treatment of highly drug-resistant infections with individualized phage preparations. Formal clinical trials with standardized products are slowly emerging. With its highly conserved genome and relative paucity of natural phage defence mechanisms <i>Mycobacterium tuberculosis</i> appears to be a suitable target for phage treatment. A phage cocktail with diverse and strictly lytic phages that kill all lineages of <i>M. tuberculosis,</i> and can be propagated on <i>Mycobacterium smegmatis</i>, has been assembled and is available for the evaluation of optimal dosage and suitable routes of administration for tuberculosis in humans. Phage treatment can be expected to be safe and active on extracellular organisms, but phage penetration to intracellular and granulomatous environments as well as synergistic effects with antibiotics are important questions to address during further evaluation.

Mycobacteriophages: From Petri dish to patient

“…However, gaining phage access to intracellular bacteria may be a challenge requiring modified delivery systems such as liposomes or “Trojan horse” strategies [ 125 – 127 ], although phage virions can be phagocytosed by macrophages, and transcytosis has been demonstrated [ 128 , 129 ]. However, there could be potential benefits to improving disease and limiting transmission by killing extracellular bacteria, in conjunction with ongoing antibiotic treatments [ 123 ]. The prevalence of highly drug resistant strains of M .…”

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline

“…MDR bacterial infections have been compounded by the COVID-19 pandemic and the emergence of the MDR strains of Clostridium difficile and Mycobacterium tuberculosis in long COVID bacterial infections [382][383][384][385][386]. Inappropriate administration of antibiotics to long COVID-19 patients despite the fact that this is not a bacterial infection may be inappropriate even when these are administered as a preventative measure against potential secondary bacterial infections that may occur and may actually result in these patients acquiring troublesome antibiotic resistant bacterial strains [387]. Antibiotic resistance is a serious problem and a major public health concern.…”

Grand challenge of antibiotics resistance: A global, multidisciplinary effort is needed

“…The role of phage, and microbial community in antibiotic resistance is very new to this field. A better understanding of the interactions between the processes across different types of environments is key to elucidating how phages mediate microbial competition and to designing efficient phage therapies in combination with antibiotics to effectively mitigate the damage of the resistant bacteria (Diacon et al, 2022). Reversing bacterial resistance to antibiotics by phage-mediated delivery of dominant sensitive genes is actively explored (Edgar et al, 2012;Sousa and Rocha, 2019).…”