Comparative homology modelling of the enzyme Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8)  in L. donovani suggest that among all of the computationally screened compounds, pentamidine, 1,3-dinitroadamantane, acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate).DNDi has a number of compounds in preclinical and phase 1 development, but no novel drugs are expected in the next 5 years. In the meantime, new combination therapies, and well as improvements to existing drugs targets, are under development. Single-dosage administrations of liposomal amphotericin B have been shown to be effective, and oral formulations are currently under development to increase access and facilitate distribution of the efficacious drug in the field.A 2018 study published details of a new potential preclinical drug candidate for the treatment for visceral leishmaniasis with an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold.There is no good vaccine candidate which prevents kala azar. A 2019 paper described designing an immunologic adjuvant which would make a VL vaccine more effective. References


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Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experiencedSince bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided. Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine. Mechanism of action
Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. It is the first member of a new class of drugs called the diarylquinolines. Bedaquiline is bactericidal. ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline. The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter. Resistance
The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance. Ongoing research
In vitro experiments have indicated that Bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis. History
Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.