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

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.

Global Burden of Fungal Infections and Antifungal Resistance from 1961 to 2024: Findings and Future Implications

“…Aspergillus species demonstrated a 1.09-fold increase in resistance while other filamentous fungi exhibited a 1.07-fold increase in resistance to natamycin per annum [135]. Resistance of fungi to other polyene macrolide antifungals including Amphotericin B has also been reported in other studies [39] [140] [141] [142] [143]. A study in the United States also reported high fluconazole-resistant candida species [143].…”

Natural infection with Leishmania (Mundinia) martiniquensis supports Culicoides peregrinus (Diptera: Ceratopogonidae) as a potential vector of leishmaniasis and characterization of a Crithidia sp. isolated from the midges

“…Using other media such as the biphasic NNN with antibiotics and performing serial dilution may allow to obtain pure promastigote cultures easily. Recently, our study regarding Amphotericin B (AmpB)-resistant L. martiniquensis parasites has suggested that the resistant strains could be more efficiently transmitted and maintained in asymptomatic hosts longer than susceptible ones (Mano et al, 2023). Thus, the isolation of parasites from is required to not only the vector competence of the insects but also the prevalence of the AmpB-resistant phenotype parasites in natural insect populations.…”

“…The prevalence of autochthonous leishmaniasis in Thailand is increasing and new cases continue to be reported (Anugulruengkitt et al, 2022;Srivarasat et al, 2022), but the natural vectors that are responsible for the transmission of the disease remain unknown. Moreover, more relapse cases caused by L. martiniquensis have been reported (Srivarasat et al, 2022;Mano et al, 2023). Various species of sand flies are known as natural vectors of Leishmania parasites in the subgenera Viannia and Leishmania (Cecílio et al, 2022).…”