Amphotericin B resistance correlates with increased fitness in vitro and in vivo in Leishmania (Mundinia) martiniquensis

Chonlada Mano; Aphisek Kongkaew; Pongsri Tippawangkosol; Pradya Somboon; Sittiruk Roytrakul; Pascale Pescher; Gerald F Späth; Chairat Uthaipibull; Adisak Tantiworawit; Padet Siriyasatien; Narissara Jariyapan

doi:10.3389/fmicb.2023.1156061

Amphotericin B resistance correlates with increased fitness in vitro and in vivo in Leishmania (Mundinia) martiniquensis

Front Microbiol. 2023 Apr 6:14:1156061. doi: 10.3389/fmicb.2023.1156061. eCollection 2023.

Affiliations

¹ Department of Parasitology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
² Animal House Unit, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
³ National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand.
⁴ Institut Pasteur, INSERM U1201, Université Paris Cité, Unité de Parasitologie Moléculaire et Signalisation, Paris, France.
⁵ Thailand Center of Excellence for Life Sciences (TCELS), Bangkok, Thailand.
⁶ Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
⁷ Center of Excellence in Vector Biology and Vector-Borne Disease, Department of Parasitology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Abstract

Amphotericin B (AmpB) deoxycholate is the available first-line drug used to treat visceral leishmaniasis caused by Leishmania (Mundinia) martiniquensis, however, some cases of AmpB treatment failure have been reported in Thailand. Resistance to drugs is known to affect parasite fitness with a potential impact on parasite transmission but still little is known about the effect of resistance to drugs on L. martiniquensis. Here we aimed to gain insight into the fitness changes occurring after treatment failure or in vitro-induced resistance to AmpB. L. martiniquensis parasites isolated from a patient before (LSCM1) and after relapse (LSCM1-6) were compared for in vitro and in vivo fitness changes together with an in vitro induced AmpB-resistant parasite generated from LSCM1 parasites (AmpBRP2i). Results revealed increased metacyclogenesis of the AmpBPR2i and LSCM1-6 strains (AmpB-resistant strains) compared to the LSCM1 strain and increased fitness with respect to growth and infectivity. The LSCM1-6 and AmpBRP2i strains were present in mice for longer periods compared to the LSCM1 strain, but no clinical signs of the disease were observed. These results suggest that the AmpB-resistant parasites could be more efficiently transmitted to humans and maintained in asymptomatic hosts longer than the susceptible strain. The asymptomatic hosts therefore may represent "reservoirs" for the resistant parasites enhancing transmission. The results in this study advocate an urgent need to search and monitor for AmpB-resistant L. martiniquensis in patients with relapsing leishmaniasis and in asymptomatic patients, especially, in HIV/Leishmania coinfected patients.

Keywords: Amphotericin B; Leishmania; Leishmania martiniquensis; Thailand; drug resistance; fitness; leishmaniasis; relapse.