Cheng, T, Kam, JY, Johansen, MD & Oehlers, SH 2020, 'High content analysis of granuloma histology and neutrophilic inflammation in adult zebrafish infected with Mycobacterium marinum', Micron, vol. 129, pp. 102782-102782.View/Download from: Publisher's site
Johansen, MD, Daher, W, Roquet-Banères, F, Raynaud, C, Alcaraz, M, Maurer, FP & Kremer, L 2020, 'Rifabutin is bactericidal against intracellular and extracellular forms of Mycobacterium abscessus.', Antimicrobial agents and chemotherapy.View/Download from: Publisher's site
Mycobacterium abscessus is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. In this context, rifabutin (RFB) has been shown to be active against M. abscessus and has raised renewed interest in using rifamycins for the treatment of M. abscessus pulmonary diseases. Herein, we compared the in vitro and in vivo activity of RFB against the smooth and rough variants of M. abscessus, differing in their susceptibility profile to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains in vitro, suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracelluar mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from M. abscessus-induced killing. This was corroborated with a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against M. abscessus both in vitro and in vivo, further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.
Johansen, MD, Herrmann, J-L & Kremer, L 2020, 'Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus', NATURE REVIEWS MICROBIOLOGY, vol. 18, no. 7, pp. 392-407.View/Download from: Publisher's site
Raynaud, C, Daher, W, Johansen, MD, Roquet-Banères, F, Blaise, M, Onajole, OK, Kozikowski, AP, Herrmann, J-L, Dziadek, J, Gobis, K & Kremer, L 2020, 'Active Benzimidazole Derivatives Targeting the MmpL3 Transporter in Mycobacterium abscessus', ACS Infectious Diseases, vol. 6, no. 2, pp. 324-337.View/Download from: Publisher's site
Raynaud, C, Daher, W, Roquet-Baneres, F, Johansen, MD, Stec, J, Onajole, OK, Ordway, D, Kozikowski, AP & Kremer, L 2020, 'Synergistic Interactions of Indole-2-Carboxamides and beta-Lactam Antibiotics against Mycobacterium abscessus', ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 64, no. 5.View/Download from: Publisher's site
Hortle, E, Johnson, KE, Johansen, MD, Nguyen, T, Shavit, JA, Britton, WJ, Tobin, DM & Oehlers, SH 2019, 'Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish.', The Journal of infectious diseases, vol. 220, no. 3, pp. 524-534.View/Download from: Publisher's site
BACKGROUND:Infection-induced thrombocytosis is a clinically important complication of tuberculosis infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. METHODS:In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for infection-induced thrombocyte activation. RESULTS:We find that the reduction in mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that infection-induced platelet activation compromises protective host immunity to mycobacterial infection. CONCLUSIONS:Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
Johansen, MD, de Silva, K, Plain, KM, Whittington, RJ & Purdie, AC 2019, 'Mycobacterium avium subspecies paratuberculosis is able to manipulate host lipid metabolism and accumulate cholesterol within macrophages', MICROBIAL PATHOGENESIS, vol. 130, pp. 44-53.View/Download from: Publisher's site
Rani, A, Viljoen, A, Johansen, MD, Kremer, L & Kumar, V 2019, 'Synthesis, anti-mycobacterial and cytotoxic evaluation of substituted isoindoline-1,3-dione-4-aminoquinolines coupled via alkyl/amide linkers', RSC Advances, vol. 9, no. 15, pp. 8515-8528.View/Download from: Publisher's site
A series of secondary amine-substituted isoindoline-1,3-dione-4-aminoquinolines were prepared via microwave heating and assayed for their anti-mycobacterial activities.
Santucci, P, Johansen, MD, Point, V, Poncin, I, Viljoen, A, Cavalier, J-F, Kremer, L & Canaan, S 2019, 'Nitrogen deprivation induces triacylglycerol accumulation, drug tolerance and hypervirulence in mycobacteria.', Scientific reports, vol. 9, no. 1.View/Download from: Publisher's site
Mycobacteria share with other actinomycetes the ability to produce large quantities of triacylglycerol (TAG), which accumulate as intracytoplasmic lipid inclusions (ILI) also known as lipid droplets (LD). Mycobacterium tuberculosis (M. tb), the etiologic agent of tuberculosis, acquires fatty acids from the human host which are utilized to synthesize TAG, subsequently stored in the form of ILI to meet the carbon and nutrient requirements of the bacterium during long periods of persistence. However, environmental factors governing mycobacterial ILI formation and degradation remain poorly understood. Herein, we demonstrated that in the absence of host cells, carbon excess and nitrogen starvation promote TAG accumulation in the form of ILI in M. smegmatis and M. abscessus, used as surrogate species of M. tb. Based on these findings, we developed a simple and reversible in vitro model to regulate ILI biosynthesis and hydrolysis in mycobacteria. We also showed that TAG formation is tgs1 dependent and that lipolytic enzymes mediate TAG breakdown. Moreover, we confirmed that the nitrogen-deprived and ILI-rich phenotype was associated with an increased tolerance towards several drugs used for treating mycobacterial infections. Importantly, we showed that the presence of ILI substantially enhanced the bacterial burden and granuloma abundance in zebrafish embryos infected with lipid-rich M. abscessus as compared to embryos infected with lipid-poor M. abscessus, suggesting that ILI are actively contributing to mycobacterial virulence and pathogenesis.
Shalini, Johansen, MD, Kremer, L & Kumar, V 2019, 'Design, synthesis, anti-mycobacterial and cytotoxic evaluation of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates.', Chemical Biology and Drug Design, vol. 94, no. 1, pp. 1300-1305.View/Download from: Publisher's site
This manuscript discloses the design and synthesis of a series of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates along with their anti-mycobacterial and cytotoxic evaluation. The present work assumes significance as it describes the first report on the amalgamation of C-4 substituted naphthalimides with various heterocyclic hydrazides. However, contrary to the rationale behind the synthesis of the conjugates, none of them inhibited the growth of Mycobacterium tuberculosis at the tested concentrations though these were non-cytotoxic towards the Vero kidney epithelial cell line.
Shalini, Johansen, MD, Kremer, L & Kumar, V 2019, 'Variedly connected 1,8-naphthalimide-7-chloroquinoline conjugates: Synthesis, anti-mycobacterial and cytotoxic evaluation', Bioorganic Chemistry, vol. 92, pp. 103241-103241.View/Download from: Publisher's site
Viljoen, A, Raynaud, C, Johansen, MD, Roquet-Baneres, F, Herrmann, J-L, Daher, W & Kremer, L 2019, 'Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in Macrophages', ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 63, no. 9.View/Download from: Publisher's site
Johansen, MD, de Silva, K, Plain, KM, Begg, DJ, Whittington, RJ & Purdie, AC 2018, 'Sheep and cattle exposed to Mycobacterium avium subspecies paratuberculosis exhibit altered total serum cholesterol profiles during the early stages of infection', VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY, vol. 202, pp. 164-171.View/Download from: Publisher's site
Johansen, MD, Hortle, E, Kasparian, JA, Romero, A, Novoa, B, Figueras, A, Britton, WJ, de Silva, K, Purdie, AC & Oehlers, SH 2018, 'Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility', FISH & SHELLFISH IMMUNOLOGY, vol. 83, pp. 238-242.View/Download from: Publisher's site
Johansen, MD, Kasparian, JA, Hortle, E, Britton, WJ, Purdie, AC & Oehlers, SH 2018, 'Mycobacterium marinum infection drives foam cell differentiation in zebrafish infection models', DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY, vol. 88, pp. 169-172.View/Download from: Publisher's site
Johansen, MD & Kremer, L, 'CFTR Depletion Confers Hypersusceptibility to Mycobacterium fortuitum in a Zebrafish Model', Frontiers in Cellular and Infection Microbiology, vol. 10.View/Download from: Publisher's site
Mycobacterium kansasii is a slow-growing nontuberculous mycobacteria responsible for coinfections particularly in patients with human immunodeficiency virus. To date, our knowledge of M. kansasii infection has been hampered owing to the lack of an effective animal model to study pathogenesis. In the current study, we showed that the zebrafish embryo is permissive to M. kansasii infection, resulting in chronic infection and formation of granulomas. On macrophage depletion, we identified M. kansasii forms extracellular cords, resulting in acute infection and rapid larval death. These findings highlight the feasibility of zebrafish for studying M. kansasii pathogenesis and for the first time identify extracellular cords in this species.