Abstract
Resistance toward current and new classes of anti-tuberculosis (anti-TB) antibiotics are rapidly emerging; thus, innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for shortening therapy regimens without inducing drug resistance. Development of new TB drugs is lengthy and expensive, and success is not guaranteed; thus, alternatives are needed. Repurposed drugs have already passed Food and Drug Administration (FDA) as well as European Medicines Agency (EMA) safety requirements and may only need to prove efficacy against Mycobacterium tuberculosis (M.tb). Phosphodiesterases (PDEs) hydrolyze the catalytic breakdown of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to their inactive mononucleotides. Advances in molecular pharmacology have identified 11 PDE families; and the success of sildenafil, a PDE-5 selective inhibitor (PDE-5i), in treating pulmonary hypertension and erectile dysfunction has invigorated research into the therapeutic potential of selective PDE inhibitors in other conditions. Myeloid-derived suppressor cells (MDSCs) suppress anti-TB T-cell responses, likely contributing to TB disease progression. PDE-5i increases cGMP within MDSC resulting in the downregulation of arginase-1 (ARG1) and nitric oxide synthase 2 (NOS2), reducing MDSC's suppressive potential. The effect of this reduction decreases MDSC-induced T-cell-suppressive mechanisms. This review highlights the possibility of HDT targeting of MDSC, using a PDE-5i in combination with the current TB regimen, resulting in improved TB treatment efficacy.
Highlights
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa
PDE-5 selective inhibitor (PDE-5i) increases cyclic guanosine monophosphate (cGMP) within Myeloid-derived suppressor cell (MDSC) resulting in the downregulation of arginase-1 (ARG1) and nitric oxide synthase 2 (NOS2), reducing MDSC’s suppressive potential
Drugs that could target MDSC directly or its associated mechanisms could prevent MDSC accumulation and function, potentially overcoming MDSC-mediated immune suppression in TB. These would include medications that would induce differentiation of MDSC into mature non-suppressive cells, inhibit MDSC expansion from hematopoietic precursors, and block MDSC signaling pathways. These strategies are currently explored in mouse models in ongoing clinical trials testing modulation of MDSC by pharmacological intervention in cancer patients, focusing on sildenafil, a substance limiting MDSC immunosuppressive function
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is among the top 10 causes of death worldwide [1]. Recent studies have illustrated multiple potential host therapeutic targets against M.tb. A comprehensive review focusing on HDT strategies to improve treatment outcome in TB highlighted preclinical studies that aimed to enhance endogenous pathways and/or limit destructive host responses. It discussed promising preclinical candidates and forerunning compounds at advanced stages of clinical investigation in TB HDT efficacy trials [8]. The development of repurposed drugs as adjunct anti-TB therapies is being actively pursued, as they would have a positive impact on treatment success rates globally
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