Leishmaniasis, the second most neglected
tropical disease, has
been reported to affect approximately 12 million people worldwide.
The causative protozoan parasite Leishmania has shown
drug resistance to available chemotherapies, owing to which we need
to look for better approaches to deal with the clinical situations.
As per recent reports, several miRNAs have been found to be differentially
expressed during Leishmania major infection
in host macrophages. We aim to evaluate the impact of miRNA-mediated
gene regulation on the key players of inflammation and macrophage
dysfunction. The origin of Leishmania miRNAs and
their processing is a questionable phenomenon as of yet. Through our
study, we aim to provide a framework of their characterization. We
amalgamate chemical systems biology and synthetic biology approaches
to identify putative miRNA targets and unravel the complexity of host–pathogen
gene regulatory networks.
Efflux pumps play a major role in the increasing antimicrobial resistance rendering a large number of drugs of no use. Large numbers of pathogens are becoming multidrug resistant due to inadequate dosage and use of the existing antimicrobials. This leads to the need for identifying new efflux pump inhibitors. Design of novel targeted therapies using inherent complexity involved in the biological network modeling has gained increasing importance in recent times. The predictive approaches should be used to determine antimicrobial activities with high pathogen specificity and microbicidal potency. Antimicrobial peptides, which are part of our innate immune system, have the ability to respond to infections and have gained much attention in making resistant strain sensitive to existing drugs. In this review paper, we outline evidences linking host-directed therapy with the efflux pump activity to infectious disease.
The emergence of drug resistance is a major concern for combating against Cutaneous Leishmaniasis, a neglected tropical disease affecting 98 countries including India. Miltefosine is the only oral drug available for the disease and Miltefosine transporter proteins play a pivotal role in the emergence of drug-resistant Leishmania major. The cause of resistance is less accumulation of drug inside the parasite either by less uptake of the drug due to a decrease in the activity of P4ATPase–CDC50 complex or by increased efflux of the drug by P-glycoprotein (P-gp, an ABC transporter). In this paper, we are trying to allosterically modulate the behavior of resistant parasite (L. major) towards its sensitivity for the existing drug (Miltefosine, a phosphatidylcholine analog). We have used computational approaches to deal with the conservedness of the proteins and apparently its three-dimensional structure prediction through ab initio modeling. Long scale membrane-embedded molecular dynamics simulations were carried out to study the structural interaction and stability. Parasite-specific motifs of these proteins were identified based on the machine learning technique, against which a peptide library was designed. The protein–peptide docking shows good binding energy of peptides Pg5F, Pg8F and PC2 with specific binding to the motifs. These peptides were tested both in vitro and in vivo, where Pg5F in combination with PC2 showed 50–60% inhibition in resistant L. major's promastigote and amastigote forms and 80–90% decrease in parasite load in mice. We posit a model system wherein the data provide sufficient impetus for being novel therapeutics in order to counteract the drug resistance phenotype in Leishmania parasites.
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