Tuberculosis (TB) remains a global healthcare crisis, with an estimated 5.8 million new cases and 1.5 million deaths in 2020. TB is caused by infection with the major human pathogen Mycobacterium tuberculosis, which is difficult to rapidly diagnose and treat. There is an urgent need for new methods of diagnosis, sufficient in vitro models that capably mimic all physiological conditions of the infection, and high-throughput drug screening platforms. Microfluidic-based techniques provide single-cell analysis which reduces experimental time and the cost of reagents, and have been extremely useful for gaining insight into monitoring microorganisms. This review outlines the field of microfluidics and discusses the use of this novel technique so far in M. tuberculosis diagnostics, research methods, and drug discovery platforms. The practices of microfluidics have promising future applications for diagnosing and treating TB.
One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis . This reservoir of bacteria is largely resistant to antimicrobial treatment that often only targets actively replicating mycobacteria, with current treatment for latent infection revolving around inhibiting the resuscitation event rather than preventing or treating latent infection. As a result, antimicrobials that target latent infection often have little to no activity in vivo. Here we report a method of in vitro analysis of physiologically relevant non-replicating persistence (NRP) utilizing cholesterol as the sole carbon source, alongside hypoxia as a driver of Mycobacterium bovis BCG into the NRP state. Using the minimal cholesterol media NRP assay, we observed an increased state of in vitro resistance to front-line anti-tubercular compounds. However, following a phenotypic screen of an approved-drug library, we identified dapsone as a bactericidal active molecule against cholesterol-dependent NRP M. bovis BCG. Through an overexpression trial of probable antimicrobial target enzymes, we further identified FolP2, a non-functional dihydropteroate synthase homologue, as the likely target of dapsone under cholesterol-NRP due to a significant increase in bacterial resistance when overexpressed. These results highlight the possible reason for little in vivo activity seen for current front-line anti-NRP drugs, and we introduce a new methodology for future drug screening as well as a potential role for dapsone inclusion within the current treatment regime.
Tuberculosis (TB) remains a global healthcare crisis with an estimated 10 million new cases and 1.4 million deaths per year TB is caused by infection with the major human pathogen Mycobacte-rium tuberculosis, which is difficult to rapidly diagnose and treat. There is an urgent need for new methods of diagnosis, sufficient in vitro models which capably mimic all physiological condi-tions of the infection, and high-throughput drug screening platforms. Microfluidic-based tech-niques provide single-cell analysis which reduces experimental time, the cost of reagents, and have been extremely useful for gaining insight into monitoring microorganisms. This review out-lines the field of microfluidics and discusses the use of this novel technique so far in M. tuberculo-sis diagnostics, research methods, and drug discovery platforms. The practices of microfluidics have promising future applications for diagnosing and treating TB.
With the ever-increasing burden of antimicrobial resistance, the demand to introduce countermeasures becomes increasingly critical. The urgency of this need is intensified by the void in antibiotic discovery, with the identification of novel compounds declining with time. Of increasing concern is Mycobacterium abscessus, which displays high levels of intrinsic resistance that lead to poor success rates, even after lengthy drug regimens. Research tackling these issues is now focused on the repurposing of preexisting drugs for antimycobacterial use, facilitating the discovery of antimicrobial compounds amidst a crisis where novel antibiotics are sparse. Part of this includes the use of combination treatments, whereby coadministration of synergistic compounds can reduce dose requirements and slow the progression of antimicrobial resistance in the long term. In this review, we will introduce the current therapeutic options for M. abscessus and provide insight into why treatment is so burdensome. We will also compile the current updates within drug repurposing for this pathogen, including the use of unconventional agents such as antimalarial drugs, the repositioning of antituberculosis candidates and the repurposing of preexisting antibiotics, including the application of combination regimens. In addition, the in vitro drug screening platforms used in their discovery will be appraised, with the view of highlighting potential future perspectives that may help increase physiological relevance. This review provides a timely appraisal of the future of M. abscessus treatment.
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