Figure 2. . The mode of action of conventional drugs against leishmaniasis and the mechanisms of drug resistance in Leishmania species.

(A) Amphotericin B affects both stages of the parasite, that is, promastigote and amastigote, mainly by binding parasite cell membrane ergosterol, which enhances cell permeability and ions influx leading to compromised cellular integrity, which eventually results in death of the parasite. In some species due to the different class of ergosterol precursor Amphotericin B fails to bind with parasites membrane leading to drug resistance. (B) Miltefosine works by inhibiting cytochrome-c oxidase beside affecting the membrane potential of mitochondria leading to the death of the parasite through apoptosis. The presence of MDR1 efflux out miltefosine drug from parasites leading to drug resistance beside poor uptake and inactivation of the drug. (C) The inhibition of active transport system through pentamidine is believed to be the mode of action of this drug, which enters the Leishmania parasite through the arginine and polyamine transporters, and gets accumulated in the mitochondria that eventually inhibits topoisomerase II. The poor accumulation of pentamidine in the mitochondria alongside drug effluxed out of the parasite through PRP1; an ATP Binding Cassette (ABC) transporter, which eventually leads to drug resistance.(D) Paromomycin inhibits protein synthesis by binding to the A-site of ribosomal RNA altering the membrane potential of mitochondria, which eventually leads to misreading of mRNA causing the parasite death. An increased vacuolar ATPase activity, which eventually efflux paromomycin out (exocytosis) of the cell in case of resistant strains. (E) Trivalent (Sb^III) and pentavalent (Sb^v) form of antimony inhibits trypanothione reductase and topoisomerase I enzymes that eventually leads to apoptosis of the Leishmania parasite. The enhanced levels of trypanothione (TSH) conjugates with the tri (Sb^III) and pentavalent (Sb^v) antimony compounds forming thiol metal conjugates that may eventually form vesicles and these vesicles are effluxed out via multidrug resistance-associated protein ABC transporter (MRPA) during antimony resistance.