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Video:Drug-resistant Leishmaniasis

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Description

Drug-resistant leishmaniasis is a growing global health issue, especially in South Asia and Latin America, where first-line drugs like pentavalent antimonials, amphotericin B and miltefosine are failing due to parasite genomic plasticity, drug efflux mechanisms and poor treatment compliance. Resistance is most severe in visceral leishmaniasis, which raises mortality risks. Current strategies focus on combination therapies, liposomal drug formulations, and oral agents and vector control.[1][2][3]

Presentation

In terms of the presentation we find that Drug-resistant leishmaniasis has the same symptoms as standard leishmaniasis:[4] Cutaneous leishmaniasis, Mucosal leishmaniasis and Visceral leishmaniasis. Resistance does not change the symptom profile, it makes the disease harder to cure and likely to relapse.[5][1]

Risk factor

As to the risk factors for Drug-resistant Leishmaniasis we find the following:[6] weakened immune response and overuse(anti-microbial medication).

Mechanism

Drug-resistant leishmaniasis develops through a combination of adaptations that reduce drug effectiveness. Mutations in transporters like aquaglyceroporin limit uptake of antimonials, while overexpression of efflux pumps such as ABC transporters expel drugs; elevated thiol compounds(glutathione) detoxify reactive intermediates; and metabolic changes alter drug targets(sterol biosynthesis for amphotericin B). This reinforced by genomic plasticity and incomplete treatment courses, allow Leishmania parasites to survive therapy.[7][8][9]

Diagnosis

As to the evaluation of Drug-resistant leishmaniasis we find the following(aside from WGS or specific gene mutation analysis(AQP1) to identify resistance markers) :[1][2][10] microscopy, culture and PCR.

Treatment

As to treatment we find that current management relies on alternatives like miltefosine. Paromomycin and pentamidine are used in certain regions, often in combination regimens to help cure rates.[11][6]

Epidemiology

As to epidemiology we find that Drug-resistant leishmaniasis has been identified in areas in South Asia, East Africa, and Latin America threatening elimination programs. One billion people live in endemic areas, with 30 to 50 thousand visceral leishmaniasis cases annually. For example, the Indian subcontinent has resistance to the first-line therapy pentavalent antimonials; this forced a shift to Miltefosine, but increasing reports of treatment failure and emerging resistance now escalate the situation.[12][13][14]

History

In terms of history we find the discovery of drug-resistant Leishmaniasis is not attributed to a single person, but rather emerged as a growing clinical problem with the failure of the primary treatment, pentavalent antimonials. The first indication and emergence of drug resistance was observed in the North Bihar state of India in the 1980s. Individuals with visceral leishmaniasis were not responding to the regimen of pentavalent antimony drugs.[5][15]

Research

A 2024 review article looks at heterocyclic scaffolds and azole antifungal agents that show preclinical anti‑leishmanial activity, with medicinal chemistry efforts focused on parasite‑selective, oral and shorter‑course candidates.[16]

References

  1. ↑ 1.0 1.1 1.2 Ponte-Sucre, Alicia; Gamarro, Francisco; Dujardin, Jean-Claude; Barrett, Michael P.; López-Vélez, Rogelio; García-Hernández, Raquel; Pountain, Andrew W.; Mwenechanya, Roy; Papadopoulou, Barbara (14 December 2017). "Drug resistance and treatment failure in leishmaniasis: A 21st century challenge". PLOS Neglected Tropical Diseases. 11 (12): e0006052. doi:10.1371/journal.pntd.0006052. PMC 5730103. PMID 29240765.
  2. ↑ 2.0 2.1 Bhusal, Chandra Kanta; Sinha, Shweta; Kaur, Davinder; Sehgal, Rakesh (2025). "Unravelling drug resistance in leishmaniasis: genomic adaptations and emerging therapies". Frontiers in Molecular Biosciences. 12 1573618. doi:10.3389/fmolb.2025.1573618. ISSN 2296-889X. PMC 12146366. PMID 40492115.
  3. ↑ Nagle, Advait; Biggart, Agnes; Be, Celine; Srinivas, Honnappa; Hein, Andreas; Caridha, Diana; Sciotti, Richard J.; Pybus, Brandon; Kreishman-Deitrick, Mara; Bursulaya, Badry; Lai, Yin H.; Gao, Mu-Yun; Liang, Fang; Mathison, Casey J. N.; Liu, Xiaodong; Yeh, Vince; Smith, Jeffrey; Lerario, Isabelle; Xie, Yongping; Chianelli, Donatella; Gibney, Michael; Berman, Ashley; Chen, Yen-Liang; Jiricek, Jan; Davis, Lauren C.; Liu, Xianzhong; Ballard, Jaime; Khare, Shilpi; Eggimann, Fabian Kurt; Luneau, Alexandre; Groessl, Todd; Shapiro, Michael; Richmond, Wendy; Johnson, Kevin; Rudewicz, Patrick J.; Rao, Srinivasa P. S.; Thompson, Christopher; Tuntland, Tove; Spraggon, Glen; Glynne, Richard J.; Supek, Frantisek; Wiesmann, Christian; Molteni, Valentina (8 October 2020). "Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases". Journal of Medicinal Chemistry. 63 (19): 10773–10781. doi:10.1021/acs.jmedchem.0c00499. ISSN 1520-4804. PMC 7549094. PMID 32667203.
  4. ↑ "Clinical Overview of Leishmaniasis". Leishmaniasis. 13 March 2024. Retrieved 11 December 2025.
  5. ↑ 5.0 5.1 Chakravarty, Jaya; Sundar, Shyam (May 2010). "Drug resistance in leishmaniasis". Journal of Global Infectious Diseases. 2 (2): 167–176. doi:10.4103/0974-777X.62887. ISSN 0974-8245. PMC 2889657. PMID 20606973.
  6. ↑ 6.0 6.1 Sundar, Shyam; Chakravarty, Jaya; Meena, Lalit P (2 January 2019). "Leishmaniasis: treatment, drug resistance and emerging therapies". Expert Opinion on Orphan Drugs. 7 (1): 1–10. doi:10.1080/21678707.2019.1552853.
  7. ↑ Singh, Neeloo; Singh, Ramsing Th.; Sundar, Shyam (15 August 2003). "Novel Mechanism of Drug Resistance in Kala Azar Field Isolates". The Journal of Infectious Diseases. 188 (4): 600–607. doi:10.1086/377133. PMID 12898450.
  8. ↑ Kamran, Mohd; Bhattacharjee, Rahul; Das, Sonali; Mukherjee, Sohitri; Ali, Nahid (6 February 2023). "The paradigm of intracellular parasite survival and drug resistance in leishmanial parasite through genome plasticity and epigenetics: Perception and future perspective". Frontiers in Cellular and Infection Microbiology. 13 1001973. doi:10.3389/fcimb.2023.1001973. ISSN 2235-2988. PMC 9939536. PMID 36814446.
  9. ↑ Zhang, Haoran; Yan, Ruixi; Liu, Yahui; Yu, Mengtao; He, Ziyi; Xiao, Junfeng; Li, Kaijie; Liu, Gang; Ning, Qin; Li, Yan (3 January 2025). "Progress in antileishmanial drugs: Mechanisms, challenges, and prospects". PLOS Neglected Tropical Diseases. 19 (1): e0012735. doi:10.1371/journal.pntd.0012735. ISSN 1935-2735. PMC 11698350. PMID 39752369.
  10. ↑ Domagalska, Malgorzata Anna; Barrett, Michael P.; Dujardin, Jean-Claude (1 April 2023). "Drug resistance in Leishmania: does it really matter?". Trends in Parasitology. 39 (4): 251–259. doi:10.1016/j.pt.2023.01.012. ISSN 1471-4922. PMID 36803859.
  11. ↑ Sundar, Shyam; Singh, Jitendra; Singh, Vishal Kumar; Agrawal, Neha; Kumar, Rajiv (31 December 2024). "Current and emerging therapies for the treatment of leishmaniasis". Expert Opinion on Orphan Drugs. 12 (1): 19–32. doi:10.1080/21678707.2024.2335248. Retrieved 13 December 2025.
  12. ↑ "Leishmaniasis". www.who.int. Archived from the original on 11 July 2025. Retrieved 7 December 2025.
  13. ↑ Hendrickx, S.; Guerin, Pj; Caljon, G.; Croft, Sl; Maes, L. (April 2018). "Evaluating drug resistance in visceral leishmaniasis: the challenges". Parasitology. 145 (4): 453–463. doi:10.1017/S0031182016002031. ISSN 0031-1820. PMC 5989324. PMID 27866478.
  14. ↑ Salari, Samira; Bamorovat, Mehdi; Sharifi, Iraj; Almani, Pooya Ghasemi Nejad (August 2022). "Global distribution of treatment resistance gene markers for leishmaniasis". Journal of Clinical Laboratory Analysis. 36 (8): e24599. doi:10.1002/jcla.24599. ISSN 1098-2825. PMC 9396204. PMID 35808933.
  15. ↑ Olliaro, Piero L.; Guerin, Philippe J.; Gerstl, Sibylle; Haaskjold, Astrid Aga; Rottingen, John-Arne; Sundar, Shyam (December 2005). "Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980-2004". The Lancet. Infectious Diseases. 5 (12): 763–774. doi:10.1016/S1473-3099(05)70296-6. ISSN 1473-3099. PMID 16310148.
  16. ↑ Masne, Tejaswini; Kumar, Dileep; Bansode, Deepali (6 September 2024). "A review of leishmaniasis: current knowledge and future directions of heterocyclic molecules". Exploration of Drug Science. 2 (5): 508–539. doi:10.37349/eds.2024.00059. ISSN 2836-7677. Retrieved 16 December 2025.
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