Minocycline Immunomodulates via Sonic Hedgehog Signaling and Apoptosis and Has Direct Potency Against Drug-Resistant Tuberculosis

Deshpande, Devyani; Pasipanodya, Jotam G.; Srivastava, Shashikant; Martin, Katherine; Athale, Shruti; Zyl, Johanna Van; Antiabong, John F.; Koeuth, Thearith; Lee, Pooi S; Dheda, Keertan; Gumbo, Tawanda

doi:10.1093/infdis/jiy587

Cited by 19 publications

(24 citation statements)

References 45 publications

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“…Thus, the neuroendocrine response pathways in the TB cavity that we describe expand the system beyond the dopamine pathway (39). Colonic inflammation in a rat model reduced hippocampal mGluR-dependent synaptic long-term depression formation, which was reversed by chronic administration of minocycline, a drug that also has direct anti-TB effect (43, 44). Moreover, Sarm1 expression decreases mGluR-dependent synaptic long-term depression formation: Sarm1 is a negative regulator of Toll-like receptor signaling, TNF-α, and antiviral cytokines production in mice (45–47).…”

Section: Discussionmentioning

confidence: 99%

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing

Dheda

Lenders

Srivastava

et al. 2019

Am J Respir Crit Care Med

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Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis. Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity. Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection ( n = 14) and healthy lung tissue from control subjects without tuberculosis ( n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways. Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm 3 (15–389 cm 3 ). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation “sink” in the central caseum–fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid–mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden ( r > 0.6), whereas T-helper effector systems did not. Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis –related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.

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Section: Discussionmentioning

confidence: 99%

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing

Dheda

Lenders

Srivastava

et al. 2019

Am J Respir Crit Care Med

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“…However, we found that Shh cannot distinguish tuberculosis and LSCC. It has been reported that Minocycline has direct potent effect against drug-resistant tuberculosis through inhibiting Hh signaling [30], which indicates that Hh signaling may be associated with tuberculosis. But the precise molecular mechanism of Hh signaling in the pathogenesis of tuberculosis needs to be uncovered.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of sonic hedgehog in lung adenocarcinoma and lung squamous cell carcinoma

Xiong

Shi

et al. 2019

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Overexpression of Sonic hedgehog (Shh) is associated with progression of several cancers. The expression of Shh in non-small cell lung cancer (NSCLC) has been reported with inconsistent results. Lung adenocarcinoma (LAC) and lung squamous cell carcinoma (LSCC) are two major subtypes of NSCLC, which have different genetic genotypes and clinical therapeutic options. The expression of Shh in specimen of patients with NSCLC has yet to be comprehensively determined according to histological subtypes. Shh expression level was determined in 167 NSCLC patients (56 LAC patients and 111 LSCC patients) by immunohistochemical assay (IHC) and disease-free survival and overall survival of patients were analyzed using the Kaplan-Meier method. Shh protein level in pleural effusion from patients with pneumonia or pleural empyema, tuberculosis, LAC and LSCC was measured with enzyme-linked immunoassay (ELISA). We found that Shh expression is increased in tumor tissues from both LAC and LSCC patients compared with the paired adjacent tissues, while Shh level is negatively correlated with tumor differentiation only in LSCC, LSCC patients containing higher-Shh expression have a poorer prognosis. Furthermore, Shh level is elevated in pleural effusion from LSCC patients compared with that of parapneumonic and LAC pleural effusion. Shh expression in tumor tissues or pleural effusion may represent a potential diagnostic and prognostic marker of LSCC patients, pleural effusion Shh may assist to distinguish between LAC and LSCC.

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“…The call to repurpose drugs used for other infections/indications, for the treatment of TB has been gaining momentum over the last decade [ 34 , 35 ]. Deshpande et al initiated a programme to identify pre-existing pharmacophores with anti-mycobacterial activity and identified ceftazidime-avibactam and benzylpenicillin as the first hits followed by minocycline [ 36 , 37 , 38 , 39 ]. Deshpande et al reported ceftazidime-avibactam to have a sterilising effect at par with standard TB therapy [ 36 ].…”

Section: Application Of Hfim In Detecting Novel or Repurposed Anti-mycobacterial Compoundsmentioning

confidence: 99%

“…Though tetracyclines are not used for the treatment of TB, the positive features of minocycline such as antibacterial potency, high bioavailability, long half-life, good distribution in lung parenchyma, high tolerance, and anti-inflammatory properties justify pre-clinical investigation into its potential as an anti-TB drug. It was found to reduce bacterial loads of both drug-susceptible and resistant strains of M. tuberculosis , most likely through apoptotic effects on host cells harbouring the bacteria and could thereby be used for active as well as latent TB [ 38 ]. Minocycline was found to be more effective in reducing MAC burden compared to standard treatment at exposures that could be achieved in a majority of patients [ 44 ].…”

Section: Application Of Hfim In Detecting Novel or Repurposed Anti-mycobacterial Compoundsmentioning

confidence: 99%

Improving the Drug Development Pipeline for Mycobacteria: Modelling Antibiotic Exposure in the Hollow Fibre Infection Model

et al. 2021

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Mycobacterial infections are difficult to treat, requiring a combination of drugs and lengthy treatment times, thereby presenting a substantial burden to both the patient and health services worldwide. The limited treatment options available are under threat due to the emergence of antibiotic resistance in the pathogen, hence necessitating the development of new treatment regimens. Drug development processes are lengthy, resource intensive, and high-risk, which have contributed to market failure as demonstrated by pharmaceutical companies limiting their antimicrobial drug discovery programmes. Pre-clinical protocols evaluating treatment regimens that can mimic in vivo PK/PD attributes can underpin the drug development process. The hollow fibre infection model (HFIM) allows for the pathogen to be exposed to a single or a combination of agents at concentrations achieved in vivo–in plasma or at infection sites. Samples taken from the HFIM, depending on the analyses performed, provide information on the rate of bacterial killing and the emergence of resistance. Thereby, the HFIM is an effective means to investigate the efficacy of a drug combination. Although applicable to a wide variety of infections, the complexity of anti-mycobacterial drug discovery makes the information available from the HFIM invaluable as explored in this review.

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Minocycline Immunomodulates via Sonic Hedgehog Signaling and Apoptosis and Has Direct Potency Against Drug-Resistant Tuberculosis

Cited by 19 publications

References 45 publications

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing

Differential expression of sonic hedgehog in lung adenocarcinoma and lung squamous cell carcinoma

Improving the Drug Development Pipeline for Mycobacteria: Modelling Antibiotic Exposure in the Hollow Fibre Infection Model

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