New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

Abate, Getahun; Ruminiski, Peter G.; Kumar, Malkeet; Singh, K. Chandramani; Hamzabegovic, Fahreta; Hoft, Daniel F.; Eickhoff, Christopher S.; Selimovic, Asmir; Campbell, Mary Ann; Chibale, Kelly

doi:10.1128/aac.01567-15

Cited by 23 publications

(27 citation statements)

References 44 publications

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“…The impermeability of the lipophilic cell wall alongside efflux mechanisms contributes to the intracellular persistence of M. tuberculosis while negatively affecting the activity of established anti-TB drugs [32].…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

et al. 2020

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Carvotacetones (1–7) isolated from Sphaeranthus africanus were screened for their antimycobacterial and efflux pump (EP) inhibitory potential against the mycobacterial model strains Mycobacterium smegmatis mc2 155, Mycobacterium aurum ATCC 23366, and Mycobacterium bovis BCG ATCC 35734. The minimum inhibitory concentrations (MICs) of the carvotacetones were detected through high-throughput spot culture growth inhibition (HT-SPOTi) and microbroth dilution assays. In order to assess the potential of the compounds 1 and 6 to accumulate ethidium bromide (EtBr) in M. smegmatis and M. aurum, a microtiter plate-based fluorometric assay was used to determine efflux activity. Compounds 1 and 6 were analyzed for their modulating effects on the MIC of EtBr and the antibiotic rifampicin (RIF) against M. smegmatis. Carvotacetones 1 and 6 had potent antibacterial effects on M. aurum and M. bovis BCG (MIC ≤ 31.25 mg/L) and could successfully enhance EtBr activity against M. smegmatis. Compound 1 appeared as the most efficient agent for impairing the efflux mechanism in M. smegmatis. Both compounds 1 and 6 were highly effective against M. aurum and M. bovis BCG. In particular, compound 1 was identified as a valuable candidate for inhibiting mycobacterial efflux mechanisms and as a promising adjuvant in the therapy of tuberculosis or other non-tubercular mycobacterial infections.

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Section: Discussionmentioning

confidence: 99%

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

et al. 2020

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“…Activation of autophagy by verapamil has been demonstrated by several groups. Initial studies evaluating the effect of verapamil and its analogs on macrophages infected with M. tuberculosis showed an association between the induction of autophagy and inhibition of intracellular replication of mycobacteria, and one of the structural analogs had an additive effect on the inhibitory antimicrobial activity of isoniazid and rifampicin [97,98]. Metformin is an antidiabetic of the biguanide class.…”

Section: Macrophage Autophagy As a Target For The Control Of The Diseasementioning

confidence: 99%

Macrophages in the Pathogenesis of Leprosy

Prata¹,

Barbosa²,

Silva³

et al. 2020

Macrophage Activation - Biology and Disease

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Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae. The disease may present different clinical forms depending on the immunological status of the host. M. leprae may infect macrophages and Schwann cells, and recent studies have demonstrated that macrophages are fundamental cells for determining the outcome of the disease. Skin lesions from patients with the paucibacillary form of the disease present a predominance of macrophages with a pro-inflammatory phenotype (M1), whereas skin lesions of multibacillary patients present a predominance of anti-inflammatory macrophages (M2). More recently, it was shown that autophagy is responsible for the control of bacillary load in paucibacillary macrophages and that the blockade of autophagy is involved in the onset of acute inflammatory reactional episodes in multibacillary cells. So, strategies that aim to induce autophagy in infected macrophages are promising not only to improve the efficacy of multidrug therapy (MDT) but also to avoid the occurrence of reactional episodes that are responsible for the disabilities observed in leprosy patients.2 production of nitric oxide, thus causing peripheral nerve damage characteristic of patients with leprosy [10]. Other studies have shown the ability of M. leprae to induce the production of oxidative mediators and their products, peroxynitrite and nitrotyrosine [11][12][13][14].Studies have demonstrated the ability of M. leprae to interact with a range of scavenger receptors of macrophages culminating in a tolerogenic response profile. The scavenger receptors are membrane receptors whose main function is the removal of molecules and cellular debris from the body, binding through a variety of polyanions, leading to phagocytosis of the target, being found in several cell types such as macrophages [15]. The ability of M. leprae to interact with the CD163 receptor, a scavenger receptor, which, during this interaction, can act as a co-receptor for M. leprae entry in macrophages, has been described [16]. It is known that activation of this receptor is related to the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), leading to the synthesis and increase of the activity of the enzyme heme oxygenase-1 (HO-1), which, through anti-inflammatory and antioxidant pathways, releases interleukin (IL)-10 and generates carbon monoxide, contributing to the polarization of these cells [17][18][19]. Bonilla and colleagues [20] demonstrated that autophagy, a mechanism of metabolic control, regulates the expression of scavenger receptors macrophage receptor with collagenous structure (MARCO) and scavenger receptor type A (SRA-I) that increase phagocytosis and NRF2 activity during Bacillus Calmette-Guérin (BCG) or M. tuberculosis (H37Rv) infection.M. leprae is able to induce macrophage SRA-I and CD36 expression [6] that contributes to the uptake of lipids, culminating in an increase in the uptake and accumulation of oxidized lipids within the macrophages, leading to a fo...

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“…Examples of autophagy promoting drugs being investigated as host-directed therapies include vitamin D [75], metformin [76,77], statins [78], verapamil [79][80][81][82][83][84][85], carbamezapine [86,87], and valproic acid [86,87]. Verapamil hydrochloride is a calcium channel antagonist that shows potential as a host-directed autophagy therapy to reduce intracellular Mycobacterium tuberculosis [79][80][81][82][83][84][85]. Norverapamil is the metabolite of verapamil and shows a similar ability to reduce intracellular bacteria in vitro [79,80].…”

Section: Therapeutics To Prevent Host Cell Subversionmentioning

confidence: 99%

“…Verapamil hydrochloride is a calcium channel antagonist that shows potential as a host-directed autophagy therapy to reduce intracellular Mycobacterium tuberculosis [79][80][81][82][83][84][85]. Norverapamil is the metabolite of verapamil and shows a similar ability to reduce intracellular bacteria in vitro [79,80]. Verapamil is being investigated as an inhalable therapy for inhalational M. tuberculosis with the verapamil-antibiotic combination demonstrating an enhanced antibacterial effect [88].…”

Section: Therapeutics To Prevent Host Cell Subversionmentioning

confidence: 99%

The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review

Laws

Taylor

Russell

et al. 2019

Expert Review of Anti-infective Therapy

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Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success. Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis. Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.

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New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

Cited by 23 publications

References 44 publications

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

Macrophages in the Pathogenesis of Leprosy

The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review

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