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Mechanisms of Action: Physiological Effects

Leishmania donovani Parasites Are Inhibited by the Benzoxaborole AN2690 Targeting Leucyl-tRNA Synthetase

Reetika Manhas, Smriti Tandon, Shib Sankar Sen, Neha Tiwari, Manoj Munde, Rentala Madhubala
Reetika Manhas
aSchool of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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Smriti Tandon
aSchool of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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Shib Sankar Sen
aSchool of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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Neha Tiwari
bSchool of Physical Sciences, Jawaharlal Nehru University, New Delhi, India
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Manoj Munde
bSchool of Physical Sciences, Jawaharlal Nehru University, New Delhi, India
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Rentala Madhubala
aSchool of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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DOI: 10.1128/AAC.00079-18
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ABSTRACT

Visceral leishmaniasis is an important public health threat in parts of India. It is caused by a protozoan parasite, Leishmania donovani. Currently available drugs manifest severe side effects. Hence, there is a need to identify new drug targets and drugs. Aminoacyl-tRNA synthetases, required for protein synthesis, are known drug targets for bacterial and fungal pathogens. The aim of the present study was to obtain essentiality data for Leishmania donovani leucyl-tRNA synthetase (LdLRS) by gene replacement. Gene replacement studies indicate that this enzyme plays an essential role in the viability of this pathogenic organism and appears to be indispensable for its survival in vitro. The heterozygous mutant parasites demonstrated a growth deficit and reduced infectivity in mouse macrophages compared to the wild-type cells. We also report that Leishmania donovani recombinant LRS displayed aminoacylation activity and that the protein localized to both the cytosol and the mitochondrion. A broad-spectrum antifungal, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), was found to inhibit parasite growth in both the promastigote and amastigote stages in vitro as well as in vivo in BALB/c mice. This compound exhibited low toxicity to mammalian cells. AN2690 was effective in inhibiting the aminoacylation activity of the recombinant LdLRS. We provide preliminary chemical validation of LdLRS as a drug target by showing that AN2690 is an inhibitor both of L. donovani LRS and of L. donovani cell growth.

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Leishmania donovani Parasites Are Inhibited by the Benzoxaborole AN2690 Targeting Leucyl-tRNA Synthetase
Reetika Manhas, Smriti Tandon, Shib Sankar Sen, Neha Tiwari, Manoj Munde, Rentala Madhubala
Antimicrobial Agents and Chemotherapy Aug 2018, 62 (9) e00079-18; DOI: 10.1128/AAC.00079-18

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Leishmania donovani Parasites Are Inhibited by the Benzoxaborole AN2690 Targeting Leucyl-tRNA Synthetase
Reetika Manhas, Smriti Tandon, Shib Sankar Sen, Neha Tiwari, Manoj Munde, Rentala Madhubala
Antimicrobial Agents and Chemotherapy Aug 2018, 62 (9) e00079-18; DOI: 10.1128/AAC.00079-18
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KEYWORDS

leucyl-tRNA synthetase
Leishmania donovani
null mutant
AN2690
antileishmanial

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