TY - JOUR
T1 - Topical Treatment for Cutaneous Leishmaniasis
T2 - Dermato-Pharmacokinetic Lead Optimization of Benzoxaboroles
AU - Van Bocxlaer, Katrien
AU - Gaukel, Eric
AU - Hauser, Deirdre
AU - Park, Seong Hee
AU - Schock, Sara
AU - Yardley, Vanessa
AU - Randolph, Ryan
AU - Plattner, Jacob J
AU - Merchant, Tejal
AU - Croft, Simon L
AU - Jacobs, Robert T
AU - Wring, Stephen A
N1 - Copyright © 2018 American Society for Microbiology.
PY - 2018/5
Y1 - 2018/5
N2 - Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 μM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 μM < EC50 < 30 μM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the in vitro evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that of para-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against Leishmania major was tested in vivo LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration.
AB - Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 μM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 μM < EC50 < 30 μM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the in vitro evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that of para-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against Leishmania major was tested in vivo LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration.
KW - Administration, Oral
KW - Administration, Topical
KW - Antiprotozoal Agents/administration & dosage
KW - Boron Compounds/administration & dosage
KW - Leishmaniasis, Cutaneous/drug therapy
U2 - 10.1128/AAC.02419-17
DO - 10.1128/AAC.02419-17
M3 - Article
C2 - 29507073
SN - 0066-4804
VL - 62
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 5
ER -